Vessela N. Kristensen

• Egeland, Nina Gran; Jonsdottir, Kristin; Aure, Miriam Ragle; Sahlberg, Kristine Kleivi; Kristensen, Vessela N.; Cronin-Fenton, Deirdre; Skaland, Ivar; Gudlaugsson, Einar; Baak, Jan P.A. & Janssen, Emiel (2020). MiR-18a and miR-18b are expressed in the stroma of oestrogen receptor alpha negative breast cancers. BMC Cancer.  ISSN 1471-2407.  20 . doi: 10.1186/s12885-020-06857-7
• Gythfeldt, Hedda von der Lippe; Lien, Tonje Gulbrandsen; Tekpli, Xavier; Silwal-Pandit, Laxmi; Borgen, Elin; Garred, Øystein; Skjerven, Helle; Schlichting, Ellen; Lundgren, Steinar; Wist, Erik; Naume, Bjørn; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian & Engebråten, Olav (2020). Immune phenotype of tumor microenvironment predicts response to bevacizumab in neoadjuvant treatment of ER-positive breast cancer. International Journal of Cancer.  ISSN 0020-7136.  147(9), s 2515- 2525 . doi: 10.1002/ijc.33108 Full text in Research Archive.
• Pladsen, Arne Valebjørg; Nilsen, Gro; Rueda, Oscar M.; Aure, Miriam Ragle; Borgan, Ørnulf; Liestøl, Knut; Vitelli, Valeria; Frigessi Di Rattalma, Arnoldo; Langerød, Anita; Mathelier, Anthony; Engebråten, Olav; Kristensen, Vessela N.; Wedge, David C.; Van Loo, Peter; Caldas, Carlos; Børresen-Dale, Anne-Lise; Russnes, Hege Elisabeth Giercksky & Lingjærde, Ole Christian (2020). DNA copy number motifs are strong and independent predictors of survival in breast cancer. Communications Biology.  ISSN 2399-3642.  3 . doi: 10.1038/s42003-020-0884-6
• Ree, Anne Hansen; Nygaard, Vigdis; Pedersen, Kjetil Boye; Heinrich, Daniel; Dueland, Svein; Bergheim, Inger Riise; Johansen, Christin; Beiske, Klaus; Negård, Anne; Lund-Iversen, Marius; Nygaard, Vegard; Hovig, Eivind; Nakken, Sigve; Nasser, Salah; Julsrud, Lars; Reisse, Claudius; Ruud, Espen Asak; Kristensen, Vessela N.; Flørenes, Vivi Ann; Geitvik, Gry; Lingjærde, Ole Christian; Børresen-Dale, Anne-Lise; Russnes, Hege Elisabeth Giercksky; Mælandsmo, Gunhild Mari & Flatmark, Kjersti (2020). Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer?the MetAction study. Acta Oncologica.  ISSN 0284-186X.  s 1- 10 . doi: 10.1080/0284186X.2020.1742377 Full text in Research Archive.
• Tahiri, Andliena; Tekpli, Xavier; Somisetty, Venkata Satheesh; DeWijn, Rik; Luders, Torben; Bukholm, Ida Rashida Khan; Hurtado, Antoni; Geisler, Jürgen & Kristensen, Vessela N. (2020). Loss of progesterone receptor is associated with distinct tyrosine kinase profiles in breast cancer. Breast Cancer Research and Treatment.  ISSN 0167-6806.  183, s 585- 598 . doi: 10.1007/s10549-020-05763-7
• Zhu, Qian; Tekpli, Xavier; Troyanskaya, Olga G. & Kristensen, Vessela N. (2020). Subtype-specific transcriptional regulators in breast tumors subjected to genetic and epigenetic alterations. Bioinformatics.  ISSN 1367-4803.  36(4), s 994- 999 . doi: 10.1093/bioinformatics/btz709 Full text in Research Archive.
• Nguyen, Chinh BKrong; Kumar, Surendra; Zucknick, Manuela; Kristensen, Vessela N.; Gjerstad, Johannes; Nilsen, Hilde Loge & Wyller, Vegard Bruun Bratholm (2019). Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome. Brain, behavior, and immunity.  ISSN 0889-1591.  76, s 82- 96 . doi: 10.1016/j.bbi.2018.11.008 Full text in Research Archive. Show summary

  Background Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. Methods We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients). Results A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score. Conclusion We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

• Bahrami, Nazli; Sauer, Torill; Engebretsen, Siri Strøm; Aljabri, Mohammad Belal; Bemanian, Vahid; Lindstrøm, Jonas Christoffer; Luders, Torben; Kristensen, Vessela N.; Lorentzen, Annika; Loeng, Marie; Ødegård, Hilde Presterud; Kvaløy, Jan Øyvind; Vestøl, Ingeborg Berge; Geisler, Stephanie; Gravdehaug, Berit; Gundersen, Joanna Majak & Geisler, Jürgen (2019). The NEOLETEXE trial: a neoadjuvant cross-over study exploring the lack of cross resistance between aromatase inhibitors. Future Oncology.  ISSN 1479-6694.  15(32), s 3675- 3682 . doi: 10.2217/fon-2019-0258 Full text in Research Archive.
• Brinkman, Arie B.; Nik-Zainal, Serena; Simmer, Femke; Rodríguez-González, F. Germán; Smid, Marcel; Alexandrov, Ludmil B.; Butler, Adam; Martin, Sancha; Davies, Helen; Glodzik, Dominik; Zou, Xueqing; Ramakrishna, Manasa; Staaf, Johan; Ringnér, Markus; Sieuwerts, Anieta; Ferrari, Anthony; Morganella, Sandro; Fleischer, Thomas; Kristensen, Vessela N.; Gut, Marta; van de Vijver, Marc J.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Thomas, Gilles; Gut, Ivo G.; Martens, John W. M.; Foekens, John A.; Stratton, Michael R. & Stunnenberg, Hendrik G. (2019). Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation. Nature Communications.  ISSN 2041-1723.  10 . doi: 10.1038/s41467-019-09828-0 Full text in Research Archive.
• Dörk, Thilo; Peterlongo, Paolo; Mannermaa, Arto; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Ahearn, Thomas; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristian J.; Augustinsson, Annelie; Freeman, Laura E. Beane; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Behrens, Sabine; Bermisheva, Marina; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Canzian, Federico; Chan, Tsun L.; Chang-Claude, Jenny; Chanock, Stephen J.; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L.; Couch, Fergus J.; Czene, Kamila; Daly, Mary B.; dos-Santos-Silva, Isabel; Dwek, Miriam; Eccles, Diana M.; Ekici, Arif B.; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; Fritschi, Lin; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Chi; Gapstur, Susan M.; García-Closas, Montserrat; García-Sáenz, José A.; Gaudet, Mia M.; Giles, Graham G.; Goldberg, Mark S.; Goldgar, David E.; Guenel, Pascal; Haeberle, Lothar; Haiman, Christopher A.; Håkansson, Niclas; Hall, Per; Hamann, Ute; Hartman, Mikael; Hauke, Jan; Hein, Alexander; Hillemanns, Peter; Hogervorst, Frans B.L.; Hooning, Maartje J.; Hopper, John L.; Howell, Tony; Huo, Dezheng; Ito, Hidemi; Iwasaki, Motoki; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Jung, Audrey; Kaaks, Rudolf; Kang, Daehee; Kapoor, Pooja Middha; Khusnutdinova, Elza; Kim, Sung-Won; Kitahara, Cari M.; Koutros, Stella; Kraft, Peter; Kristensen, Vessela N.; Kwong, Ava; Lambrechts, Diether; Le Marchand, Loïc; Li, Jingmei; Lindström, Sara; Linet, Martha; Lo, Wing-Yee; Long, Jirong; Lophatananon, Artitaya; Lubiński, Jan; Manoochehri, Mehdi; Manoukian, Siranoush; Margolin, Sara; Martinez, Elena; Matsuo, Keitaro; Mavroudis, Dimitris; Meindl, Alfons; Menon, Usha; Milne, Roger L.; Mohd Taib, Nur Aishah; Muir, Kenneth; Mulligan, Anna Marie; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Newman, William G.; Offit, Kenneth; Olopade, Olufunmilayo I.; Olshan, Andrew F.; Olson, Janet E.; Olsson, Håkan; Park, Sue K.; Park-Simon, Tjoung-Won; Peto, Julian; Plaseska-Karanfilska, Dijana; Pohl-Rescigno, Esther; Presneau, Nadege; Rack, Brigitte; Radice, Paolo; Rashid, Muhammad Usman; Rennert, Gad; Rennert, Hedy S.; Romero, Atocha; Ruebner, Matthias; Saloustros, Emmanouil; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schneider, Michael O.; Schoemaker, Minouk J.; Scott, Christopher; Shen, Chen-Yang; Shu, Xiao-Ou; Simard, Jacques; Slager, Susan; Smichkoska, Snezhana; Southey, Melissa C.; Spinelli, John J.; Stone, Jennifer; Surowy, Harald; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William J.; Teo, Soo H.; Terry, Mary Beth; Toland, Amanda E.; Tollenaar, Robert A.E.M.; Torres, Diana; Torres-Mejía, Gabriela; Troester, Melissa A.; Truong, Thérèse; Tsugane, Shoichiro; Untch, Michael; Vachon, Celine M.; van den Ouweland, Ans M.W.; van Veen, Elke M.; Vijai, Joseph; Wendt, Camilla; Wolk, Alicja; Yu, Jyh-Cherng; Zheng, Wei; Ziogas, Argyrios; Ziv, Elad; Dunning, Alison M.; Pharoah, Paul D.P.; Schindler, Detlev; Devilee, Peter & Easton, Douglas F. (2019). Two truncating variants in FANCC and breast cancer risk. Scientific Reports.  ISSN 2045-2322.  9, s 1- 14 . doi: 10.1038/s41598-019-48804-y Full text in Research Archive.
• Escala-Garcia, Maria; Guo, Qi; Dörk, Thilo; Canisius, Sander; Keeman, Renske; Dennis, Joe; Beesley, Jonathan; Lecarpentier, Julie; Bolla, Manjeet K.; Wang, Qin; Abraham, Jean; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Auer, Paul L.; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Boeckx, Bram; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brenner, Hermann; Brentnall, Adam; Brinton, Louise; Broberg, Per; Brock, Ian W.; Brucker, Sara Y.; Burwinkel, Barbara; Caldas, Carlos; Caldés, Trinidad; Campa, Daniele; Canzian, Federico; Carracedo, Angel; Carter, Brian D.; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Cheng, Ting-Yuan David; Chin, Suet-Feung; Clarke, Christine L.; Cordina-Duverger, Emilie; Couch, Fergus J.; Cox, David G.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dunn, Janet A.; Dunning, Alison M.; Durcan, Lorraine; Dwek, Miriam; Earl, Helena M.; Ekici, Arif B.; Eliassen, A. Heather; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Figueroa, Jonine; Flesch-Janys, Dieter; Flyger, Henrik; Gabrielson, Marike; Gago-Dominguez, Manuela; Galle, Eva; Gapstur, Susan M.; García-Closas, Montserrat; García-Sáenz, José A.; Gaudet, Mia M.; George, Angela; Georgoulias, Vassilios; Giles, Graham G.; Glendon, Gord; Goldgar, David E.; Gonzalez-Neira, Anna; Grenaker, Grethe Irene; Grip, Mervi; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hall, Per; Hamann, Ute; Hankinson, Susan; Harkness, Elaine F.; Harrington, Patricia A.; Hart, Steven N.; Hartikainen, Jaana M.; Hein, Alexander; Hillemanns, Peter; Hiller, Louise; Holleczek, Bernd; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Huang, Guanmengqian; Humphreys, Keith; Hunter, David J.; Janni, Wolfgang; John, Esther M.; Jones, Michael E.; Jukkola-Vuorinen, Arja; Jung, Audrey; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kerin, Michael J.; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I.; Kitahara, Cari M.; Knight, Julia A.; Ko, Yon-Dschun; Koppert, Linetta B.; Kosma, Veli-Matti; Kraft, Peter; Kristensen, Vessela N.; Krüger, Ute; Kuhl, Tabea; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lejbkowicz, Flavio; Li, Lian; Lindblom, Annika; Lindström, Sara; Linet, Martha; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Lubiński, Jan; Lux, Michael P.; MacInnis, Robert J.; Maierthaler, Melanie; Maishman, Tom; Makalic, Enes; Mannermaa, Arto; Manoochehri, Mehdi; Manoukian, Siranoush; Margolin, Sara; Martinez, Maria Elena; Mavroudis, Dimitrios; McLean, Catriona; Meindl, Alfons; Middha, Pooja; Miller, Nicola; Milne, Roger L.; Moreno, Fernando; Mulligan, Anna Marie; Mulot, Claire; Nassir, Rami; Neuhausen, Susan L.; Newman, William T.; Nielsen, Sune F.; Nordestgaard, Børge G.; Norman, Aaron; Olsson, Håkan; Orr, Nick; Pankratz, V. Shane; Park-Simon, Tjoung-Won; Pérez, Jose I.A.; Pérez-Barrios, Clara; Peterlongo, Paolo; Petridis, Christos; Pinchev, Mila; Prajzendanc, Karoliona; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Ramachandran, Dhanya; Rennert, Gadi; Rennert, Hedy S.; Rhenius, Valerie; Romero, Atocha; Roylance, Rebecca; Saloustros, Emmanouil; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schumacher, Fredrick; Schwentner, Lukas; Scott, Rodney J.; Scott, Christopher; Seynaeve, Caroline; Shah, Mitul; Simard, Jacques; Smeets, Ann; Sohn, Christof; Southey, Melissa C.; Swerdlow, Anthony J.; Talhouk, Aline; Tamimi, Rulla M.; Tapper, William J.; Teixeira, Manuel R.; Tengström, Maria; Terry, Mary Beth; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Turman, Constance; Turnbull, Clare; Ulmer, Hans-Ulrich; Untch, Michael; Vachon, Celine; van Asperen, Christi J.; van den Ouweland, Ans M.W.; van Veen, Elke M.; Wendt, Camilla; Whittemore, Alice S.; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Yang, Xiaohong R.; Zhang, Yan; Easton, Douglas F.; Fasching, Peter A.; Nevanlinna, Heli; Eccles, Diana M.; Pharoah, Paul D.P. & Schmidt, Marjanka K. (2019). Genome-wide association study of germline variants and breast cancer-specific mortality. British Journal of Cancer.  ISSN 0007-0920.  120(6), s 647- 657 . doi: 10.1038/s41416-019-0393-x Full text in Research Archive.
• Ferreira, Manuel A.; Gamazon, Eric R.; Al-Ejeh, Fares; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arason, Adalgeir; Arndt, Volker; Aronson, Kristian J.; Arun, Banu K.; Asseryanis, Ella; Azzollini, Jacopo; Balmaña, Judith; Barnes, Daniel R.; Barrowdale, Daniel; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Białkowska, Katarzyna; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borg, Åke; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Caldés, Trinidad; Caligo, Maria A.; Campa, Daniele; Campbell, Ian; Canzian, Federico; Carter, Jonathan; Carter, Brian D.; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Christiansen, Hans; Chung, Wendy K.; Claes, Kathleen B.M.; Clarke, Christine L.; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; de la Hoya, Miguel; Dennis, Joe; Devilee, Peter; Diez, Orland; Dörk, Thilo; Dunning, Alison M.; Dwek, Miriam; Eccles, Diana M.; Ejlertsen, Bent; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A.; Fletcher, Olivia; Flyger, Henrik; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gago-Dominguez, Manuela; Ganz, Patricia A.; Gapstur, Susan M.; Garber, Judy; García-Closas, Montserrat; García-Sáenz, José A.; Gaudet, Mia M.; Giles, Graham G.; Glendon, Gord; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; He, Wei; Heyworth, Jane; Hogervorst, Frans B.L.; Hollestelle, Antoinette; Hoover, Robert N.; Hopper, John L.; Hulick, Peter J.; Humphreys, Keith; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakimovska, Milena; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; Jankowitz, Rachel C.; John, Esther M.; Johnson, Nichola; Joseph, Vijai; Karlan, Beth Y.; Khusnutdinova, Elza; Kiiski, Johanna I.; Ko, Yon-Dschun; Jones, Michael E.; Konstantopoulou, Irene; Kristensen, Vessela N.; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Lindström, Sara; Long, Jirong; Loud, Jennifer T.; Lubiński, Jan; Makalic, Enes; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Maurer, Tabea; Mavroudis, Dimitrios; McGuffog, Lesley; Meindl, Alfons; Menon, Usha; Michailidou, Kyriaki; Miller, Austin; Montagna, Marco; Moreno, Fernando; Moserle, Lidia; Mulligan, Anna Marie; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nevelsteen, Ines; Nielsen, Finn C.; Nikitina-Zake, Liene; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olsson, Håkan; Osorio, Ana; Papp, Janos; Park-Simon, Tjoung-Won; Parsons, Michael T.; Pedersen, Inge Søkilde; Peixoto, Ana; Peterlongo, Paolo; Pharoah, Paul D.P.; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Presneau, Nadege; Radice, Paolo; Rantala, Johanna; Rennert, Gad; Risch, Harvey A.; Saloustros, Emmanouil; Sanden, Kristin; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Sharma, Priyanka; Shu, Xiao-Ou; Simard, Jacques; Singer, Christian F.; Soucy, Penny; Southey, Melissa C.; Spinelli, John J.; Spurdle, Amanda B.; Stone, Jennifer; Swerdlow, Anthony J.; Tapper, William J.; Taylor, Jack A.; Teixeira, Manuel R.; Terry, Mary Beth; Teulé, Alex; Thomassen, Mads; Thöne, Kathrin; Thull, Darcy L.; Tischkowitz, Marc; Toland, Amanda E.; Torres, Diana; Truong, Thérèse; Tung, Nadine; Vachon, Celine M.; van Asperen, Christi J.; van den Ouweland, Ans M.W.; van Rensburg, Elizabeth J.; Vega, Ana; Viel, Alessandra; Wang, Qin; Wappenschmidt, Barbara; Weitzel, Jeffrey N.; Wendt, Camilla; Winqvist, Robert; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Ziogas, Argyrios; Kraft, Peter; Antoniou, Antoniou C.; Zheng, Wei; Easton, Douglas F.; Milne, Roger L.; Beesley, Jonathan & Chenevix-Trench, Georgia (2019). Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nature Communications.  ISSN 2041-1723.  10(1741) . doi: 10.1038/s41467-018-08053-5 Full text in Research Archive. Show summary

  Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in nonbreast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

• Jiang, Xia; Finucane, Hilary K.; Schumacher, Fredrick R.; Schmit, Stephanie L.; Tyrer, Jonathan P.; Han, Younghun; Michailidou, Kyriaki; Lesseur, Corina; Kuchenbaecker, Karoline B.; Dennis, Joe; Conti, David V.; Casey, Graham; Gaudet, Mia M.; Huyghe, Jeroen R.; Albanes, Demetrius; Aldrich, Melinda C.; Andrew, Angeline S.; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Antonenkova, Natalia N.; Arnold, Susanne M.; Aronsen, Kristan J.; Arun, Banu K.; Bandera, Elisa V.; Barkardottir, Rosa B.; Barnes, Daniel R.; Batra, Jyotsna; Beckmann, Matthias W.; Benitez, Javier; Benlloch, Sara; Berchuck, Andrew; Berndt, Sonja I.; Bickeboller, Heike; Bien, Stephanie A.; Blomqvist, Carl; Boccia, Stefania; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brenton, James D.; Brook, Mark N.; Brunet, Joan; Brunnström, Hans; Buchanan, Daniel D.; Burwinkel, Barbara; Butzow, Ralf; Cadoni, Gabriella; Caldés, Trinidad; Caligo, Maria A.; Campbell, Ian; Campbell, Peter T.; Cancel-Tassin, Geraldine; Cannon-Albright, Lisa; Campa, Daniele; Caporaso, Neil; Carvalho, André L.; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Chu; Christiani, David C.; Claes, Kathleen B.M.; Claessens, Frank; Clements, Judith; Collée, J. Margriet; Correa, Marcia Cruz; Couch, Fergus J.; Cox, Angela; Cunningham, Julie M.; Cybulski, Cezary; Czene, Kamila; Daly, Mary B.; deFazio, Anna; Devilee, Peter; Diez, Orland; Gago-Dominguez, Manuela; Donovan, Jenny L.; Dörk, Thilo; Duell, Eric J.; Dunning, Alison M.; Dwek, Miriam; Eccles, Diana M.; Edlund, Christopher K.; Edwards, Digna R. Velez; Ellberg, Carolina; Evans, D. Gareth; Fasching, Peter A.; Ferris, Robert L.; Liloglou, Triantafillos; Figueiredo, Jane C.; Fletcher, Olivia; Fortner, Renée T.; Fostira, Florentia; Franceschi, Silvia; Friedman, Eitan; Gallinger, Steven J.; Ganz, Patricia A.; Garber, Judy; García-Sáenz, José A.; Gayther, Simon A.; Giles, Graham G.; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; Goode, Ellen L.; Goodman, Marc T.; Goodman, Gary; Grankvist, Kjell; Greene, Mark H.; Grönberg, Henrik; Gronwald, Jacek; Guénel, Pascal; Håkansson, Niclas; Hall, Per; Hamann, Ute; Hamdy, Freddie C.; Hamilton, Robert J.; Hampe, Jochen; Haugen, Aage; Heitz, Florian; Herrero, Rolando; Hillemanns, Peter; Hoffmeister, Michael; Høgdall, Estrid; Hong, Yun-Chul; Hopper, John L.; Houlston, Richard; Hulick, Peter J.; Hunter, David J.; Huntsman, David G.; Idos, Gregory; Imyanitov, Evgeny N.; Ingles, Sue Ann; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Jenkins, Mark A.; Johansson, Mattias; Johansson, Mikael; John, Esther M.; Joshi, Amit D.; Kaneva, Radka; Karlan, Beth Y.; Kelemen, Linda E.; Kuhl, Tabea; Khaw, Kay-Tee; Khusnutdinova, Elza; Kibel, Adam S.; Kiemeney, Lambertus A.; Kim, Jeri; Kjær, Susanne K.; Knight, Julia A.; Kogevinas, Manolis; Kote-Jarai, Zsofia; Koutros, Stella; Kristensen, Vessela N.; Kupryjanczyk, Jolanta; Lacko, Martin; Lam, Stephan; Lambrechts, Diether; Landi, Maria Teresa; Lazarus, Philip; Le, Nhu D.; Lee, Eunjung; Lejbkowicz, Flavio; Lenz, Heinz-Josef; Leslie, Goska; Lessel, Davor; Lester, Jenny; Levine, Douglas A.; Li, Li; Li, Christopher I.; Lindblom, Annika; Lindor, Noralane M.; Liu, Geoffrey; Loupakis, Fotios; Lubinski, Jan; Mæhle, Lovise Olaug; Maier, Christiane; Mannermaa, Arto; Marchand, Loic Le; Margolin, Sara; May, Taymaa; McGuffog, Lesley; Meindl, Alfons; Middha, Pooja; Miller, Austin; Milne, Roger L.; MacInnis, Robert J.; Modugno, Francesmary; Montagna, Marco; Moreno, Victor; Moysich, Kirsten B.; Mucci, Lorelei; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L.; Neal, David E.; Ness, Andrew R.; Neuhausen, Susan L.; Nevanlinna, Heli; Newcomb, Polly A.; Newcomb, Lisa F.; Nielsen, Finn Cilius; Nikitina-Zake, Liene; Nordestgaard, Børge G.; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Olama, Ali Amin Al; Olopade, Olufunmilayo I.; Olshan, Andrew F.; Olsson, Håkan; Osorio, Ana; Pandha, Hardev; Park, Jong Y.; Pashayan, Nora; Parsons, Michael T.; Pejovic, Tanja; Penney, Kathryn L.; Peters, Wilbert H.M.; Phelan, Catherine M.; Phipps, Amanda I.; Plaseska-Karanfilska, Dijana; Pring, Miranda; Prokofyeva, Darya; Radice, Paolo; Stefansson, Kari; Ramus, Susan J.; Raskin, Leon; Rennert, Gad; Rennert, Hedy S.; van Rensburg, Elizabeth J.; Riggan, Marjorie J.; Risch, Harvey A.; Risch, Angela; Roobol, Monique J.; Rosenstein, Barry S.; Rossing, Mary Anne; De Ruyck, Kim; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schabath, Matthew B.; Schleutker, Johanna; Schmidt, Marjanka K.; Setiawan, V. Wendy; Shen, Hongbing; Siegel, Erin M.; Sieh, Weiva; Singer, Christian F.; Slattery, Marthaa L.; Sørensen, Karina Dalsgaard; Southey, Melissa C.; Spurdle, Amanda B.; Stanford, Janet L.; Stevens, Victoria L.; Stintzing, Sebastian; Stone, Jennifer; Sundfeldt, Karin; Sutphen, Rebecca; Swerdlow, Anthony J.; Tajara, Eloiza H; Tangen, Catherine M.; Tardon, Adonina; Taylor, Jack A.; Teare, M. Dawn; Teixeira, Manuel; Terry, Mary Beth; Terry, Kathryn L.; Thibodeau, Stephen N.; Thomassen, Mads; Bjørge, Line; Tischkowitz, Marc; Toland, Amanda E.; Torres, Diana; Townsend, Paul A.; Travis, Ruth C.; Tung, Nadine; Tworoger, Shelley S.; Ulrich, Cornelia M.; Usmani, Nawaid; Vachon, Celine M.; Van Nieuwenhuysen, Els; Vega, Ana; Aguado-Barrera, Miguel Elias; Wang, Qin; Webb, Penelope M.; Weinberg, Clarice R.; Weinstein, Stephanie; Weissler, Mark C.; Weitzel, Jeffrey N.; West, Catharine M.L.; White, Emily; Whittemore, Alice S.; Wichmann, H.-Erich; Wiklund, Fredrik; Winqvist, Robert; Wolk, Alicja; Woll, Penella; Woods, Michael; Wu, Anna H.; Wu, Xifeng; Yannoukakos, Drakoulis; Zheng, Wei; Zienolddiny, Shanbeh; Ziogas, Argyrios; Zorn, Kristin K.; Lane, Jacqueline M.; Saxena, Richa; Thomas, Duncan; Hung, Rayjean J.; Diergaarde, Brenda; McKay, James; Peters, Ulrike; Hsu, Li; García-Closas, Montserrat; Eeles, Rosalind A.; Chenevix-Trench, Georgia; Brennan, Paul J.; Haiman, Christopher A.; Simard, Jacques; Easton, Douglas F.; Gruber, Stephen B.; Pharoah, Paul D.P.; Price, Alkes L.; Pasaniuc, Bogdan; Amos, Christopher I.; Kraft, Peter & Lindström, Sara (2019). Shared heritability and functional enrichment across six solid cancers. Nature Communications.  ISSN 2041-1723.  10:431, s 1- 23 . doi: 10.1038/s41467-018-08054-4 Full text in Research Archive. Show summary

  Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

• Johansson, Henrik J.; Socciarelli, Fabio; Vacanti, Nathaniel M.; Haugen, Mads Haugland; Zhu, Yafeng; Siavelis, Ioannis; Fernandez-Woodbridge, Alejandro; Aure, Miriam Ragle; Sennblad, Bengt; Vesterlund, Mattias; Branca, Rui M.; Orre, Lukas M.; Huss, Mikael; Fredlund, Erik; Beraki, Else; Garred, Øystein; Boekel, Jorrit; Sauer, Torill; Zhao, Wei; Nord, Silje; Møller, Elen Kristine; Jans, Daniel C.; Brismar, Hjalmar; Haukaas, Tonje Husby; Bathen, Tone Frost; Schlichting, Ellen; Naume, Bjørn; Luders, Torben; Borgen, Elin; Kristensen, Vessela N.; Russnes, Hege Elisabeth Giercksky; Lingjærde, Ole Christian; Mills, Gordon B.; Sahlberg, Kristine Kleivi; Børresen-Dale, Anne-Lise & Lehtiö, Janne (2019). Breast cancer quantitative proteome and proteogenomic landscape. Nature Communications.  ISSN 2041-1723.  10:1600, s 1- 14 . doi: 10.1038/s41467-019-09018-y Full text in Research Archive.
• Lai, Xiaoran; Geier, Oliver; Fleischer, Thomas; Garred, Øystein; Borgen, Elin; Funke, Simon Wolfgang; Kumar, Surendra; Rognes, Marie Elisabeth; Seierstad, Therese; Børresen-Dale, Anne-Lise; Kristensen, Vessela N.; Engebråten, Olav; Kohn Luque, Alvaro & Frigessi Di Rattalma, Arnoldo (2019). Towards personalized computer simulation of breast cancer treatment: a multi-scale pharmacokinetic and pharmacodynamic model informed by multi-type patient data. Cancer Research.  ISSN 0008-5472.  79(16), s 4293- 4304 . doi: 10.1158/0008-5472.CAN-18-1804 Full text in Research Archive.
• Lee, Young-suk; Krishnan, Arjun; Oughtred, Rose; Rust, Jennifer; Chang, Christie S.; Ryu, Joseph; Kristensen, Vessela N.; Dolinski, Kara; Theesfeld, Chandra L. & Troyanskaya, Olga G. (2019). A Computational Framework for Genome-wide Characterization of the Human Disease Landscape. Cell Systems.  ISSN 2405-4712.  8(2), s 152- 162.e6 . doi: 10.1016/j.cels.2018.12.010
• Levy-Jurgenson, Alona; Tekpli, Xavier; Kristensen, Vessela N. & Yakhini, Zohar (2019). Predicting Methylation from Sequence and Gene Expression Using Deep Learning with Attention. Lecture Notes in Computer Science (LNCS).  ISSN 0302-9743.  11488 LNBI, s 179- 190 . doi: 10.1007/978-3-030-18174-1_13
• Lindholm, Evita Maria; Aure, Miriam Ragle; Haugen, Mads Haugland; Sahlberg, Kristine Kleivi; Kristensen, Vessela N.; Nebdal, Daniel J.H.; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian & Engebråten, Olav (2019). miRNA expression changes during the course of neoadjuvant bevacizumab and chemotherapy treatment in breast cancer. Molecular Oncology.  ISSN 1574-7891.  13(10), s 2278- 2296 . doi: 10.1002/1878-0261.12561 Full text in Research Archive.
• Nome, Marianne Eikhom; Euceda, Leslie R.; Jabeen, Shakila; Debik, Julia; Bathen, Tone Frost; Giskeødegård, Guro F.; Tasken, Kristin Austlid; Mælandsmo, Gunhild Mari; Halvorsen, Bente; Yndestad, Arne; Borgen, Elin; Garred, Øystein; Aukrust, Pål; Ueland, Thor; Engebråten, Olav; Kristensen, Vessela N. & Tekpli, Xavier (2019). Serum levels of inflammation-related markers and metabolites predict response to neoadjuvant chemotherapy with and without bevacizumab in breast cancers. International Journal of Cancer.  ISSN 0020-7136.  146(1), s 223- 235 . doi: 10.1002/ijc.32638 Full text in Research Archive.
• Parashar, Deepak; Geethadevi, Anjali; Aure, Miriam Ragle; Mishra, Jyotsna; George, Jasmine; Chen, Changliang; Mishra, Manoj K.; Tahiri, Andliena; Zhao, Wei; Nair, Bindu; Lu, Yiling; Mangala, Lingegowda S.; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Camara, Amadou K.S.; Liang, Mingyu; Rader, Janet S.; Ramchandran, Ramani; You, Ming; Sood, Anil K.; Kristensen, Vessela N.; Mills, Gordon B.; Pradeep, Sunila & Chaluvally-Raghavan, Pradeep Chaluvally-Raghavan (2019). miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer. Cell reports.  ISSN 2211-1247.  29(13), s 4389- 4406.e10 . doi: 10.1016/j.celrep.2019.11.085
• Shu, Xiang; Wu, Lang; Khankari, Nikhil K.; Shu, Xiao-Ou; Wang, Thomas J; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Milne, Roger L; Schmidt, Marjanka K; Pharoah, Paul DP; Andrulis, Irene L; Hunter, David J; Simard, Jacques; Easton, Douglas F; Zheng, Wei; Beeghly-Fadiel, Alicia J; Honda, Anton-Culver; Antonenkova, Natalia N; Volker, Arndt; Aronson, Kristan J; Auer, Paul L; Barrdahl, Myrto; Baynes, Caroline; Beane Freeman, Laura E; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brucker, Sara Y.; Brüning, Thomas; Burwinkel, Barbara; Cai, Qiuyin; Calde´s, Trinidad; Canzian, Federico; Carter, Brian D.; Castelao, Jose E.; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ting-Yuan David; Clarke, Christine L.; Kristensen, Vessela N. & Ziv, Elad (2019). Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.. International Journal of Epidemiology.  ISSN 0300-5771.  48(3), s 795–- 806 . doi: 10.1093/ije/dyy201
• Tekpli, Xavier; Lien, Tonje Gulbrandsen; Røssevold, Andreas Hagen; Nebdal, Daniel J.H.; Borgen, Elin; Ohnstad, Hege Oma; Kyte, Jon A; Vallon-Christersson, Johan; Fongaard, Marie; Due, Eldri Undlien; Svartdal, Lisa Gregusson; Sveli, My Anh Tu; Garred, Øystein; Frigessi Di Rattalma, Arnoldo; Sahlberg, Kristine Kleivi; Sørlie, Therese; Russnes, Hege Elisabeth Giercksky; Naume, Bjørn & Kristensen, Vessela N. (2019). An independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment. Nature Communications.  ISSN 2041-1723.  10:5499, s 1- 14 . doi: 10.1038/s41467-019-13329-5 Full text in Research Archive.
• Václavíková, Radka; Klajic, Jovana; Brynychová, Veronika; Elsnerova, Katerina; Grenaker, Grethe Irene; Tost, Jörg; Kristensen, Vessela N.; Rob, Lukáŝ; Kodet, Roman; Škapa, Petr; Mrhalová, Marcela & Souček, Pavel (2019). Development of high-resolution melting analysis for ABCB1 promoter methylation: Clinical consequences in breast and ovarian carcinoma. Oncology Reports.  ISSN 1021-335X.  42(2), s 763- 774 . doi: 10.3892/or.2019.7186
• Bemanian, Vahid; Noone, John Christopher; Sauer, Torill; Touma, Joel Joul; Vetvik, Katja K; Söderberg-Naucler, Cecilia; Lindstrøm, Jonas Christoffer; Bukholm, Ida Rashida Khan; Kristensen, Vessela N. & Geisler, Jürgen (2018). Somatic EP300-G211S mutations are associated with overall somatic mutational patterns and breast cancer specific survival in triple-negative breast cancer. Breast Cancer Research and Treatment.  ISSN 0167-6806.  2, s 339- 351 . doi: 10.1007/s10549-018-4927-3
• Jabeen, Shakila; Espinoza, Jaime; Torland, Lilly Anne; Zucknick, Manuela; Kumar, Surendra; Haakensen, Vilde Drageset; Luders, Torben; Engebraaten, Olav; Børresen-Dale, Anne-Lise; Kyte, Jon A; Gromov, Pavel; Naume, Bjørn; Kristensen, Vessela N.; Gromova, Irina & Tekpli, Xavier (2018). Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics.. Oncoimmunology.  ISSN 2162-4011.  :e1537691 . doi: 10.1080/2162402X.2018.1537691 Full text in Research Archive.
• Jabeen, Shakila; Zucknick, Manuela; Nome, Marianne Eikhom; dannenfelser, ruth; Fleischer, Thomas; Kumar, Surendra; Luders, Torben; Gythfeldt, Hedda; Troyanskaya, Olga; Kyte, Jon A; Børresen-Dale, Anne-Lise; Naume, Bjørn; Tekpli, Xavier; Engebråten, Olav & Kristensen, Vessela N. (2018). Serum cytokine levels in breast cancer patients during neoadjuvant treatment with bevacizumab. Oncoimmunology.  ISSN 2162-4011.  7(11), s e1457598-1- e1457598-15 . doi: 10.1080/2162402X.2018.1457598
• Mauger, Florence; Kernaleguen, Magali; Lallemand, Céline; Kristensen, Vessela N.; Deleuze, Jean-François & Tost, Jörg (2018). Enrichment of methylated molecules using enhanced-ice-co-amplification at lower denaturation temperature-PCR (E-ice-COLD-PCR) for the sensitive detection of disease-related hypermethylation. Epigenomics.  ISSN 1750-1911.  10(5), s 525- 537 . doi: 10.2217/epi-2017-0166
• Mavaddat, Nasim; Michailidou, Kyriaki; Dennis, Joe; Lush, Michael; Fachal, Laura; Lee, Andrew; Tyrer, Jonathan P.; Chen, Ting-Huei; Wang, Qin; Bolla, Manjeet K.; Yang, Xin; Adank, Muriel A.; Ahearn, Thomas; Kristiina, Aittomäki; Allen, Jamie; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristian J.; Auer, Paul L.; Auvinen, Päivi; Barrdahl, Myrto; Freeman, Laura E Beane; Beckman, Matthias W.; Behrens, Sabine; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Bremer, Michael; Brenner, Hermann; Brentnall, Adam; Brock, Ian W.; Brooks-Wilson, Angela; Brucker, Sara Y.; Brüning, Thomas; Burwinkel, Barbara; Campa, Daniele; Carter, Brian D.; Castelao, Jose E.; Chanock, Stephen J.; Chlebowski, Rowan; Christiansen, Hans; Clarke, Christine L.; Collée, J. Margriet; Cordina-Duverger, Emilie; Cornelissen, Sten; Kristensen, Vessela N.; García-Closas, Montserrat; Simard, Jacques & Easton, Douglas F. (2018). Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. American Journal of Human Genetics.  ISSN 0002-9297.  104(1), s 21- 34 . doi: 10.1016/j.ajhg.2018.11.002 Show summary

  Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

• Møller, Elen Kristine; Nord, Silje; Wedge, David C; Lingjærde, Ole Christian; Silwal-Pandit, Laxmi; Gythfeldt, Hedda; Vollan, Hans Kristian Moen; Fleischer, Thomas; Krohn, Marit; Schlichting, Ellen; Borgen, Elin; Garred, Øystein; Holmen, Marit Muri; Wist, Erik; Naume, Bjørn; Van Loo, Peter; Børresen-Dale, Anne-Lise; Engebråten, Olav & Kristensen, Vessela N. (2018). Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations. Genome Medicine.  ISSN 1756-994X.  10:92 . doi: 10.1186/s13073-018-0601-y Full text in Research Archive.
• O'Mara, Tracy A.; Glubb, Dylan M.; Amant, Frédéric; Annibali, Daniela; Ashton, Katie; Attia, John; Auer, Paul L.; Beckmann, Matthias W.; Black, Amanda; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Buchanan, Daniel D.; Burwinkel, Barbara; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Chu; Chen, Maxine M.; Cheng, Timothy H.T.; Clarke, Christine L.; Clendenning, Mark; Cook, Linda S.; Couch, Fergus J.; Cox, Angela; Crous-Bous, Marta; Czene, Kamila; Day, Felix; Dennis, Joe; Depreeuw, Jeroen; Doherty, Jennifer Anne; Dörk, Thilo; Dowdy, Sean C.; Dürst, Matthias; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Friedenreich, Christine M.; Fritschi, Lin; Fung, Jenny; García-Closas, Montserrat; Gaudet, Mia M.; Giles, Graham G.; Goode, Ellen L.; Gorman, Maggie; Haiman, Christopher A.; Hall, Per; Hankison, Susan E.; Healey, Catherine S.; Hein, Alexander; Hillemanns, Peter; Hodgson, Shirley; Høivik, Erling Andre; Holliday, Elizabeth G.; Hopper, John L.; Hunter, David J.; Jones, Angela; Krakstad, Camilla; Kristensen, Vessela N.; Lambrechts, Diether; Marchand, Loic Le; Liang, Xiaolin; Lindblom, Annika; Lissowska, Jolanta; Long, Jirong; Lu, Lingeng; Magliocco, Anthony M.; Martin, Lynn; McEvoy, Mark; Meindl, Alfons; Michailidou, Kyriaki; Milne, Roger L.; Mints, Miriam; Montgomery, Grant W.; Nassir, Rami; Olsson, Håkan; Orlow, Irene; Otton, Geoffrey; Palles, Claire; Perry, John R.B.; Peto, Julian; Pooler, Loreall; Prescott, Jennifer; Proietto, Tony; Rebbeck, Timothy R.; Risch, Harvey A.; Rogers, Peter A.W.; Rübner, Matthias; Runnebaum, Ingo; Sacerdote, Carlotta; Sarto, Gloria E.; Schumacher, Fredrick; Scott, Rodney J.; Setiawan, V. Wendy; Shah, Mitul; Sheng, Xin; Shu, Xiao-Ou; Southey, Melissa C.; Swerdlow, Anthony J.; Tham, Emma; Trovik, Jone; Turman, Constance; Tyrer, Jonathan P.; Vachon, Celine; VanDen Berg, David; Vanderstichele, Adriaan; Wang, Zhaoming; Webb, Penelope M.; Wentzensen, Nicolas; Werner, Henrica Maria Johanna; Winham, Stacey J.; Wolk, Alicja; Xia, Lucy; Xiang, Yong-Bing; Yang, Hannah P.; Yu, Herbert; Zheng, Wei; Pharoah, Paul D.P.; Dunning, Alison M.; Kraft, Peter; De Vivo, Immaculata; Tomlinson, Ian; Easton, Douglas F.; Spurdle, Amanda B. & Thompson, Deborah J. (2018). Identification of nine new susceptibility loci for endometrial cancer. Nature Communications.  ISSN 2041-1723.  9:3166, s 1- 12 . doi: 10.1038/s41467-018-05427-7 Full text in Research Archive.
• Painter, Jodie N.; O'Mara, Tracy A.; Morris, Andrew P.; Cheng, Timothy H.T.; Gorman, Maggie; Martin, Lynn; Hodson, Shirley; Jones, Angela; Martin, Nicholas G.; Gordon, Scott; Henders, Anjali K.; Attia, John; McEvoy, Mark; Holliday, Elizabeth G.; Scott, Rodney J.; Webb, Penelope M.; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Rübner, Matthias; Hall, Per; Czene, Kamila; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Lambrechts, Diether; Amant, Frédéric; Annibali, Daniela; Depreeuw, Jeroen; Vanderstichele, Adriaan; Goode, Ellen L.; Cunningham, Julie M.; Dowdy, Sean C.; Winham, Stacey J.; Trovik, Jone; Høivik, Erling Andre; Werner, Henrica Maria Johanna; Krakstad, Camilla; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Tham, Emma; Mints, Miriam; Ahmed, Shahana; Healey, Catherine S.; Shah, Mitul; Pharoah, Paul D.P.; Dunning, Alison M.; Dennis, Joe; Bolla, Manjeet K.; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P.; Hopper, John L; Peto, Julian; Swerdlow, Anthony J.; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J.; Giles, Graham G.; Kristensen, Vessela N.; Cox, Angela; Zondervan, Krina T.; Nyholt, Dale R.; MacGregor, Stuart; Montgomery, Grant W.; Tomlinson, Ian; Easton, Douglas F.; Thompson, Deborah J. & Spurdle, Amanda B. (2018). Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses. Cancer Medicine.  ISSN 2045-7634.  7(5), s 1978- 1987 . doi: 10.1002/cam4.1445
• Prasmickaite, Lina; Tenstad, Ellen; Pettersen, Solveig; Jabeen, Shakila; Egeland, Eivind Valen; Nord, Silje; Pandya, Abhilash D.; Haugen, Mads Haugland; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Engebråten, Olav & Mælandsmo, Gunhild Mari (2018). Basal-like breast cancer engages tumor-supportive macrophages via secreted factors induced by extracellular S100A4. Molecular Oncology.  ISSN 1574-7891.  12(9), s 1540- 1558 . doi: 10.1002/1878-0261.12319 Full text in Research Archive.
• Tahiri, Andliena; Aure, Miriam Ragle & Kristensen, Vessela N. (2018). MicroRNA Networks in Breast Cancer Cells. Methods in molecular biology.  ISSN 1064-3745.  1711, s 55- 81 . doi: 10.1007/978-1-4939-7493-1_4 Show summary

  A variety of molecular techniques can be used in order to unravel the molecular composition of cells. In particular, the microarray technology has been used to identify novel biomarkers that may be useful in the diagnosis, prognosis, or treatment of cancer. The microarray technology is ideal for biomarker discovery as it allows for the screening of a large number of molecules at once. In this review, we focus on microRNAs (miRNAs) which are key molecules in cells and regulate gene expression post-transcriptionally. miRNAs are small, single-stranded RNA molecules that bind to complementary mRNAs. Binding of miRNAs to mRNAs leads either to degradation, or translational inhibition of the target mRNA. Roughly one third of all the mRNAs are postulated to be regulated by miRNAs. miRNAs are known to be deregulated in different types of cancer, including breast cancer, and it has been demonstrated that deregulation of several miRNAs can be used as biological markers in cancer. miRNA expression can for example discriminate between normal, benign and malignant breast tissue, and between different breast cancer subtypes. In the post-genomic era, an important task of molecular biology is to understand gene regulation in the context of biological networks. Because miRNAs have such a pronounced role in cells, it is pivotal to understand the mechanisms that underlie their control, and to identify how miRNAs influence cancer development and progression.

• Tinholt, Mari; Garred, Øystein; Borgen, Elin; Beraki, Else; Schlichting, Ellen; Kristensen, Vessela N.; Sahlberg, Kristine Kleivi & Iversen, Nina (2018). Subtype-specific clinical and prognostic relevance of tumor-expressed F5 and regulatory F5 variants in breast cancer: the CoCaV study. Journal of Thrombosis and Haemostasis.  ISSN 1538-7933.  16(7), s 1347- 1356 . doi: 10.1111/jth.14151
• Wu, Lang; Shi, Wei; Long, Jirong; Guo, Xingyi; Michailidou, Kyriaki; Beesley, Jonathan; Bolla, Manjeet K.; Shu, Xiao-Ou; Lu, Yingchang; Cai, Qiuyin; Al-Ejeh, Fares; Rozali, Esdy; Wang, Qin; Dennis, Joe; Li, Bingshan; Zeng, Chenjie; Feng, Helian; Gusev, Alexander; Barfield, Richard T.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristian J.; Auer, Paul L.; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W.; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brucker, Sara Y.; Burwinkel, Barbara; Caldés, Trinidad; Canzian, Federico; Carter, Brian D.; Castelao, Jose Esteban; Chang-Claude, Jenny; Chen, Xiaoqing; Cheng, Ting-Yuan David; Christiansen, Hans; Clarke, Christine L.; Collée, Margriet; Cornelissen, Sten; Couch, Fergus J.; Cox, David; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Doheny, Kimberly F.; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Dwek, Miriam; Eccles, Diana M.; Eilber, Ursula; Eliassen, A. Heather; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gabrielson, Marike; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Closas, Montserrat; Gaudet, Mia M.; Ghoussaini, Maya; Giles, Graham G.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Guénel, Pascal; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hall, Per; Hallberg, Emily; Hamann, Ute; Harrington, Patricia; Hein, Alexander; Hicks, Belynda; Hillemanns, Peter; Hollestelle, Antoinette; Hoover, Robert N.; Hopper, John L.; Huang, Guanmengqian; Humphreys, Keith; Hunter, David J.; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Johnson, Nichola; Jones, Kristine; Jones, Michael E.; Jung, Audrey; Kaaks, Rudolf; Kerin, Michael J.; Khusnutdinova, Elza; Kosma, Veli-Matti; Kristensen, Vessela N.; Lambrechts, Diether; Le Marchand, Loic; Li, Jingmei; Lindström, Sara; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Lubinski, Jan; Luccarini, Craig; Lux, Michael P.; MacInnis, Robert J.; Maishman, Tom; Kostovska, Ivana Maleva; Mannermaa, Arto; Manson, JoAnn E.; Margolin, Sara; Mavroudis, Dimitrios; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Meyer, Jeffery; Mulligan, Anna Marie; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F.; Nordestgaard, Børge G.; Olopade, Olufunmilayo I.; Olson, Janet E.; Olsson, Håkan; Peterlongo, Paolo; Peto, Julian; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gad; Rennert, Hedy S.; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Rudolph, Anja; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schneeweiss, Andreas; Scott, Rodney J.; Scott, Christopher G.; Seal, Sheila; Shah, Mitul; Shrubsole, Martha J.; Smeets, Ann; Southey, Melissa C.; Spinelli, John J.; Stone, Jennifer; Surowy, Harald; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William; Taylor, Jack A.; Terry, Mary Beth; Tessier, Daniel C.; Thomas, Abigail; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Torres, Diana; Truong, Thérèse; Untch, Michael; Vachon, Celine; Van Den Berg, David; Vincent, Daniel; Waisfisz, Quinten; Weinberg, Clarice R.; Wendt, Camilla; Whittemore, Alice S.; Wildiers, Hans; Willett, Walter C.; Winqvist, Robert; Wolk, Alicja; Xia, Lucy; Yang, Xiaohong R.; Ziogas, Argyrios; Ziv, Elad; Dunning, Alison M.; Pharoah, Paul D.P.; Simard, Jacques; Milne, Roger L.; Edwards, Stacey L.; Kraft, Peter; Easton, Douglas F.; Chenevix-Trench, Georgia & Zheng, Wei (2018). A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer. Nature Genetics.  ISSN 1061-4036.  50(7), s 968- 978 . doi: 10.1038/s41588-018-0132-x
• Aure, Miriam Ragle; Vitelli, Valeria; Jernström, Sandra Johanna; Kumar, Surendra; Krohn, Marit; Due, Eldri Undlien; Haukaas, Tonje Husby; Leivonen, Suvi-Katri; Vollan, Hans Kristian Moen; Luders, Torben; Rødland, Einar Andreas; Vaske, Charles; Zhao, Wei; Møller, Elen Kristine; Nord, Silje; Giskeødegård, Guro F.; Bathen, Tone Frost; Caldas, Carlos; Tramm, Trine; Alsner, Jan; Overgaard, Jens; Geisler, Jürgen; Bukholm, Ida Rashida Khan; Naume, Bjørn; Schlichting, Ellen; Sauer, Torill; Mills, Gordon B.; Kåresen, Rolf; Mælandsmo, Gunhild; Lingjærde, Ole Christian; Frigessi, Arnoldo; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Sahlberg, Kristine Kleivi & OSBREAC, Oslo Breast Cancer Consortium (2017). Integrative clustering reveals a novel split in the luminal A subtype of breast cancer with impact on outcome. Breast Cancer Research.  ISSN 1465-5411.  19 . doi: 10.1186/s13058-017-0812-y Full text in Research Archive. Show summary

  Background Breast cancer is a heterogeneous disease at the clinical and molecular level. In this study we integrate classifications extracted from five different molecular levels in order to identify integrated subtypes. Methods Tumor tissue from 425 patients with primary breast cancer from the Oslo2 study was cut and blended, and divided into fractions for DNA, RNA and protein isolation and metabolomics, allowing the acquisition of representative and comparable molecular data. Patients were stratified into groups based on their tumor characteristics from five different molecular levels, using various clustering methods. Finally, all previously identified and newly determined subgroups were combined in a multilevel classification using a “cluster-of-clusters” approach with consensus clustering. Results Based on DNA copy number data, tumors were categorized into three groups according to the complex arm aberration index. mRNA expression profiles divided tumors into five molecular subgroups according to PAM50 subtyping, and clustering based on microRNA expression revealed four subgroups. Reverse-phase protein array data divided tumors into five subgroups. Hierarchical clustering of tumor metabolic profiles revealed three clusters. Combining DNA copy number and mRNA expression classified tumors into seven clusters based on pathway activity levels, and tumors were classified into ten subtypes using integrative clustering. The final consensus clustering that incorporated all aforementioned subtypes revealed six major groups. Five corresponded well with the mRNA subtypes, while a sixth group resulted from a split of the luminal A subtype; these tumors belonged to distinct microRNA clusters. Gain-of-function studies using MCF-7 cells showed that microRNAs differentially expressed between the luminal A clusters were important for cancer cell survival. These microRNAs were used to validate the split in luminal A tumors in four independent breast cancer cohorts. In two cohorts the microRNAs divided tumors into subgroups with significantly different outcomes, and in another a trend was observed. Conclusions The six integrated subtypes identified confirm the heterogeneity of breast cancer and show that finer subdivisions of subtypes are evident. Increasing knowledge of the heterogeneity of the luminal A subtype may add pivotal information to guide therapeutic choices, evidently bringing us closer to improved treatment for this largest subgroup of breast cancer.

• Bjørklund, Sunniva Maria Stordal; Panda, Anshuman; Kumar, Surendra; Seiler, Michael; Robinson, Doug; Gheeya, Jinesh; Yao, Ming; Grenaker, Grethe Irene; Toppmeyer, Deborah; Riis, Margit; Naume, Bjørn; Børresen-Dale, Anne-Lise; Kristensen, Vessela N.; Ganesan, Shridar & Bhanot, Gyan (2017). Widespread alternative exon usage in clinically distinct subtypes of Invasive Ductal Carcinoma. Scientific Reports.  ISSN 2045-2322.  7(1) . doi: 10.1038/s41598-017-05537-0 Full text in Research Archive.
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason; Russnes, Hege Elisabeth Giercksky; Pandey, Bina P.; Nilsen, Gro; Nord, Silje; Bignell, Graham R; White, Kevin P.; Børresen-Dale, Anne-Lise; Campbell, Peter J.; Kristensen, Vessela N.; Stratton, Michael R.; Lingjærde, Ole Christian; Moreau, Yves & Van Loo, Peter (2017). Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors. Nature Communications.  ISSN 2041-1723.  8:1221, s 1- 14 . doi: 10.1038/s41467-017-01355-0 Full text in Research Archive.
• Clancy, Trevor; dannenfelser, ruth; Troyanskaya, Olga G.; Malmberg, Karl-Johan; Hovig, Eivind & Kristensen, Vessela N. (2017). Bioinformatics approaches to profile the tumor microenvironment for immunotherapeutic discovery. Current pharmaceutical design.  ISSN 1381-6128.  23(32), s 4716- 4725 . doi: 10.2174/1381612823666170710154936 Full text in Research Archive. Show summary

  In the microenvironment of a malignancy, tumor cells do not exist in isolation, but rather in a diverse ecosystem consisting not only of heterogeneous tumor-cell clones, but also normal cell types such as fibroblasts, vasculature, and an extensive pool of immune cells at numerous possible stages of activation and differentiation. This results in a complex interplay of diverse cellular signaling systems, where the immune cell component is now established to influence cancer progression and therapeutic response. It is experimentally difficult and laborious to comprehensively and systematically profile these distinct cell types from heterogeneous tumor samples in order to capitalize on potential therapeutic and biomarker discoveries. One emerging solution to address this challenge is to computationally extract cell-type specific information directly from bulk tumors. Such in silico approaches are advantageous because they can capture both the cell-type specific profiles and the tissue systems level of cell-cell interactions. Accurately and comprehensively predicting these patterns in tumors is an important challenge to overcome, not least given the success of immunotherapeutic drug treatment of several human cancers. This is especially challenging for subsets of closely related immune cell phenotypes with relatively small gene expression differences, which have critical functional distinctions. Here, we outline the existing and emerging novel bioinformatics strategies that can be used to profile the tumor immune landscape.

• dannenfelser, ruth; Nome, Marianne Eikhom; Tahiri, Andliena; Ursini-Siegel, Josie; Vollan, Hans Kristian Moen; Haakensen, Vilde Drageset; Helland, Åslaug; Naume, Bjørn; Caldas, Carlos; Børresen-Dale, Anne-Lise; Kristensen, Vessela N. & Troyanskaya, Olga G. (2017). Data-driven analysis of immune infiltrate in a large cohort of breast cancer and its association with disease progression, ER activity, and genomic complexity. OncoTarget.  ISSN 1949-2553.  8(34), s 57121- 57133 . doi: 10.18632/oncotarget.19078 Full text in Research Archive. Show summary

  The tumor microenvironment is now widely recognized for its role in tumor progression, treatment response, and clinical outcome. The intratumoral immunological landscape, in particular, has been shown to exert both pro-tumorigenic and anti-tumorigenic effects. Identifying immunologically active or silent tumors may be an important indication for administration of therapy, and detecting early infiltration patterns may uncover factors that contribute to early risk. Thus far, direct detailed studies of the cell composition of tumor infiltration have been limited; with some studies giving approximate quantifications using immunohistochemistry and other small studies obtaining detailed measurements by isolating cells from excised tumors and sorting them using flow cytometry. Herein we utilize a machine learning based approach to identify lymphocyte markers with which we can quantify the presence of B cells, cytotoxic T-lymphocytes, T-helper 1, and T-helper 2 cells in any gene expression data set and apply it to studies of breast tissue. By leveraging over 2,100 samples from existing large scale studies, we are able to find an inherent cell heterogeneity in clinically characterized immune infiltrates, a strong link between estrogen receptor activity and infiltration in normal and tumor tissues, changes with genomic complexity, and identify characteristic differences in lymphocyte expression among molecular groupings. With our extendable methodology for capturing cell type specific signal we systematically studied immune infiltration in breast cancer, finding an inverse correlation between beneficial lymphocyte infiltration and estrogen receptor activity in normal breast tissue and reduced infiltration in estrogen receptor negative tumors with high genomic complexity.

• Fleischer, Thomas; Tekpli, Xavier; Mathelier, Anthony; Wang, Shixiong; Nebdal, Daniel J.H.; Dhakal, Hari Prasad; Sahlberg, Kristine Kleivi; Schlichting, Ellen; Børresen-Dale, Anne-Lise; Borgen, Elin; Naume, Bjørn; Eskeland, Ragnhild; Frigessi, Arnoldo; Tost, Jörg; Rodriguez, Antoni Hurtado & Kristensen, Vessela N. (2017). DNA methylation at enhancers identifies distinct breast cancer lineages. Nature Communications.  ISSN 2041-1723.  8(1379) . doi: 10.1038/s41467-017-00510-x Full text in Research Archive.
• Guo, Qi; Burgess, Stephen; Turman, Constance; Bolla, Manjeet K; Wang, Qin; Lush, Michael; Abraham, Jean; Aittomäki, Kristiina; Andrulis, Irene L; Apicella, Carmel; Arndt, Volker; Barrdahl, Myrto; Benitez, Javier; Berg, Christine D; Blomqvist, Carl; Bojesen, Stig E; Bonanni, Bernardo; Brand, Judith S; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Caldas, Carlos; Campa, Daniele; Canzian, Federico; Chang-Claude, Jenny; Chanock, Stephen J; Chin, Suet-Feung; Couch, Fergus J; Cox, Angela; Cross, Simon S; Cybulski, Cezary; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Diver, W Ryan; Dunning, Alison M; Earl, Helena M.; Eccles, Diana M; Ekici, Arif B; Eriksson, Mikael; Evans, D Gareth; Fasching, Peter A; Kristensen, Vessela N.; Chenevix-Trench, Georgia; Dörk, Thilo; Easton, Douglas F; García-Closas, Montserrat; Kraft, Peter; Hopper, John L; Zheng, Wei; Schmidt, Marjanka K & Pharoah, Paul DP (2017). Body mass index and breast cancer survival: a Mendelian randomization analysis. International Journal of Epidemiology.  ISSN 0300-5771.  46(6), s 1814- 1822 . doi: 10.1093/ije/dyx131 Full text in Research Archive. Show summary

  Background<br/> There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.<br/><br/> Methods<br/> We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.<br/><br/> Results<br/> BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01–1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89–1.13, P = 0.95).<br/><br/> Conclusions<br/> Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

• Helland, Thomas; Henne, Nina; Bifulco, Ersilia; Naume, Bjørn; Borgen, Elin; Kristensen, Vessela N.; Kvaløy, Jan Terje; Lash, Timothy L; Grenaker, Grethe Irene; van Schaik, RHN; Janssen, Emiel; Hustad, Simon Steinar; Lien, Ernst Asbjørn; Mellgren, Gunnar & Søiland, Håvard (2017). Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients. Breast Cancer Research.  ISSN 1465-5411.  19(1) . doi: 10.1186/s13058-017-0916-4 Full text in Research Archive. Show summary

  Background Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. Methods From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome. Results Breast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14–11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05–13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35–13.58, and HR = 3.70, 95% CI = 1.03–13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information. Conclusions Patients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted.

• Jiao, Xiang; Aravidis, Christos; Marikkannu, Rajeshwari; Rantala, Johanna; Picelli, Simone; Adamovic, Tatjana; Liu, Tao; Maguire, Paula; Kremeyer, Barbara; Luo, Liping; von Holst, Susanna; Kontham, Vinaykumar; Thutkawkorapin, Jessada; Margolin, Sara; Du, Quan; Lundin, Johanna; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Ambrosone, Christine B.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Beckmann, Matthias W.; Blomqvist, Carl; Blot, William; Boeckx, Bram; Bojesen, Stig E.; Bonanni, Bernardo; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Cai, Qiuyin; Chang-Claude, Jenny; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Deming-Halverson, Sandra L.; Devilee, Peter; dos-Santos-Silva, Isabel; Dörk, Thilo; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Flyger, Henrik; Gabrielson, Marike; García-Closas, Montserrat; Giles, Graham G.; González-Neira, Anna; Guénel, Pascal; Guo, Qi; Gündert, Melanie; Haiman, Christopher A.; Hallberg, Emily; Hamann, Ute; Harrington, Patricia; Hooning, Maartje J.; Hopper, John L; Huang, Guanmengqian; Jakubowska, Anna; Jones, Michael E.; Kerin, Michael J.; Kosma, Veli-Matti; Kristensen, Vessela N.; Lambrechts, Diether; Marchand, Loic Le; Lubinski, Jan; Mannermaa, Arto; Martens, John W.M.; Meindl, Alfons; Milne, Roger L.; Mulligan, Anna Marie; Neuhausen, Susan L.; Nevanlinna, Heli; Peto, Julian; Pylkäs, Katri; Radice, Paolo; Rhenius, Valerie; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Seynaeve, Caroline; Shah, Mitul; Simard, Jacques; Southey, Melissa C.; Swerdlow, Anthony J; Truong, Thérèse; Wendt, Camilla; Winqvist, Robert; Zheng, Wei; Benitez, Javier; Dunning, Alison M.; Pharoah, Paul D.P.; Easton, Douglas F.; Czene, Kamila; Hall, Per & Lindblom, Annika (2017). PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1. OncoTarget.  ISSN 1949-2553.  8(61), s 102769- 102782 . doi: 10.18632/oncotarget.21800 Full text in Research Archive. Show summary

  Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.

• Michailidou, Kyriaki; Lindström, Sara; Dennis, Joe; Beesley, Jonathan; Hui, Shirley; Kar, Siddhartha; Lemacon, Audrey; Soucy, Penny; Glubb, Dylan; Rostamianfar, Asha; Bolla, Manjeet K.; Wang, Qin; Tyrer, Jonathan; Dicks, Ed; Lee, Andrew; Wang, Zhaoming; Allen, Jamie; Keeman, Renske; Eilber, Ursula; French, Juliet D.; Chen, Xiao Qing; Fachal, Laura; McCue, Karen; Reed, Amy E. McCart; Ghoussaini, Maya; Carroll, Jason S.; Jiang, Xia; Finucane, Hilary; Adams, Marcia; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristian J.; Arun, Banu; Auer, Paul L; Bacot, François; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brand, Judith S.; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brock, Ian W.; Broeks, Annegien; Brooks-Wilson, Angela; Brucker, Sara Y.; Brüning, Thomas; Burwinkel, Barbara; Butterbach, Katja; Cai, Qiuyin; Cai, Hui; Caldés, Trinidad; Canzian, Federico; Carracedo, Angel; Carter, Brian D.; Castelao, Jose E.; Chan, Tsun L.; Cheng, Ting-Yuan David; Chia, Kee Seng; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L.; Collee, Margriet; Conroy, Don M.; Cordina-Duverger, Emilie; Cornelissen, Sten; Cox, David G.; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Doheny, Kimberly F.; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M.; Ekici, Arif B.; Eliassen, A. Heather; Ellberg, Carolina; Elvira, Mingajeva; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gaborieau, Valerie; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Yu-Tang; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Georgoulias, Vassilios; Giles, Graham G.; Glendon, Gord; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Grenaker, Grethe Irene; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Harrington, Patricia; Hart, Steven N.; Hartikainen, Jaana M.; Hartman, Mikael; Hein, Alexander; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Ho, Dona N.; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Hou, Ming-Feng; Hsiung, Chia-Ni; Huang, Guanmengqian; Humphreys, Keith; Ishiguro, Junko; Ito, Hidemi; Iwasaki, Motoki; Iwata, Hiroji; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kasuga, Yoshio; Kerin, Michael J.; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I.; Kim, Sung-Won; Knight, Julia A.; Kosma, Veli-Matti; Kristensen, Vessela N.; Krüger, Ute; Kwong, Ava; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lee, Min Hyuk; Lee, Jong Won; Lee, Chuen Neng; Lejbkowicz, Flavio; Li, Jingmei; Lilyquist, Jenna; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Luccarini, Craig; Lux, Michael P.; Ma, Edmond S.K.; MacInnis, Robert J.; Maishman, Tom; Makalic, Enes; Malone, Kathleen E.; Kostovska, Ivana Maleva; Mannermaa, Arto; Manoukian, Siranoush; Manson, JoAnn E.; Margolin, Sara; Mariapun, Shivaani; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; McKay, James; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Menéndez, Primitiva; Menon, Usha; Meyer, Jeffery; Miao, Hui; Miller, Nicola; Taib, Nur Aishah Mohd; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F.; Noh, Dong-Young; Nordestgaard, Børge G.; Norman, Aaron; Olopade, Olufunmilayo I.; Olson, Janet E.; Olsson, Håkan; Olswold, Curtis; Orr, Nick; Pankratz, V. Shane; Park, Sue K.; Park-Simon, Tjoung-Won; Lloyd, Rachel; Perez, Jose I.A.; Peterlongo, Paolo; Peto, Julian; Phillips, Kelly-Anne; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Pugh, Elizabeth; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gadi; Rennert, Hedy S.; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Ruddy, Kathryn J.; Rüdiger, Thomas; Rudolph, Anja; Ruebner, Matthias; Rutgers, Emiel J.T.; Saloustros, Emmanouil; Sandler, Dale P.; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schumacher, Fredrick; Schürmann, Peter; Scott, Rodney J.; Scott, Christopher; Seal, Sheila; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Grace; Sherman, Mark E.; Shrubsole, Martha J.; Shu, Xiao-Ou; Smeets, Ann; Sohn, Christof; Southey, Melissa C.; Spinelli, John J.; Stegmaier, Christa; Stewart-Brown, Sarah; Stone, Jennifer; Stram, Daniel O.; Surowy, Harald; Swerdlow, Anthony; Tamimi, Rulla; Taylor, Jack A.; Tengström, Maria; Teo, Soo H.; Terry, Mary Beth; Tessier, Daniel C.; Thanasitthichai, Somchai; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Tong, Ling; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Tsugane, Shoichiro; Ulmer, Hans-Ulrich; Ursin, Giske; Untch, Michael; Vachon, Celine; Van Asperen, Christi J.; Van Den Berg, David; van den Ouweland, Ans M.W.; Van Der Kolk, Lizet; van der Luijt, Rob B.; Vincent, Daniel; Vollenweider, Jason; Waisfisz, Quinten; Wang-Gohrke, Shan; Weinberg, Clarice R.; Wendt, Camilla; Whittemore, Alice S.; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H.; Xia, Lucy; Yamaji, Taiki; Yang, Xiaohong R.; Yip, Cheng Har; Yoo, Keun-Young; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Lakhani, Sunil R.; Antoniou, Antonis C.; Droit, Arnaud; Andrulis, Irene L.; Amos, Christopher I.; Couch, Fergus J.; Pharoah, Paul D.P.; Chang-Claude, Jenny; Hall, Per; Hunter, David J.; Milne, Roger L.; García-Closas, Montserrat; Schmidt, Marjanka K.; Chanock, Stephen J.; Dunning, Alison M.; Edwards, Stacey L.; Bader, Gary D.; Chenevix-Trench, Georgia; Simard, Jacques; Kraft, Peter & Easton, Douglas F. (2017). Association analysis identifies 65 new breast cancer risk loci. Nature.  ISSN 0028-0836.  551(7678), s 92- 94 . doi: 10.1038/nature24284 Show summary

  Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10−8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

• Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Bader, Gary D.; Pharoah, Paul D P; Couch, Fergus J; Easton, Douglas F; Kraft, Peter; Chenevix-Trench, Georgia; Garcia-Closas, Montserrat; Schmidt, Marjanka K; Antoniou, Antonis C; Simard, Jacques; Børresen-Dale, Anne-Lise; Grenaker, Grethe Irene & Kristensen, Vessela N. (2017). Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nature Genetics.  ISSN 1061-4036.  49(12), s 1767- 1778 . doi: 10.1038/ng.3785 Show summary

  Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

• Muranen, Taru A.; Greco, Dario; Blomqvist, Carl; Aittomäki, Kristiina; Khan, Sofia; Hogervorst, Frans; Verhoef, Senno; Pharoah, Paul D.P.; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Bojesen, Stig E.; Nordestgaard, Børge G.; Schoemaker, Minouk; Swerdlow, Anthony; Garcia-Closas, Montserrat; Figueroa, Jonine; Dörk, Thilo; Bogdanova, Natalia V.; Hall, Per; Li, Jingmei; Khusnutdinova, Elza; Bermisheva, Marina; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Peto, Julian; Dos Santos Silva, Isabel; Couch, Fergus J.; Olson, Janet E.; Hillemans, Peter; Park-Simon, Tjoung-Won; Brauch, Hiltrud; Hamann, Ute; Burwinkel, Barbara; Marme, Frederik; Meindl, Alfons; Schmutzler, Rita K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor J.; Tomlinson, Ian; Lambrechts, Diether; Moisse, Matthieu; Lindblom, Annika; Margolin, Sara; Hollestelle, Antoinette; Martens, John W.M.; Fasching, Peter A.; Beckmann, Matthias W.; Andrulis, Irene L.; Knight, Julia A.; Anton-Culver, Hoda; Ziogas, Argyrios; Giles, Graham G.; Milne, Roger L.; Brenner, Hermann; Arndt, Volker; Mannermaa, Arto; Kosma, Veli-Matti; Chang-Claude, Jenny; Rudolph, Anja; Devilee, Peter; Seynaeve, Caroline; Hopper, John L.; Southey, Melissa C.; John, Esther M.; Whittemore, Alice S.; Bolla, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Dennis, Joe; Easton, Douglas F.; Schmidt, Marjanka K. & Nevanlinna, Heli (2017). Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genetics in Medicine.  ISSN 1098-3600.  19(5), s 599- 603 . doi: 10.1038/gim.2016.147
• Ohnstad, Hege Oma; Borgen, Elin; Falk, Ragnhild Sørum; Lien, Tonje Gulbrandsen; Aaserud, Marit; Sveli, My Anh Tu; Kyte, Jon A; Kristensen, Vessela N.; Geitvik, Gry; Schlichting, Ellen; Wist, Erik; Sørlie, Therese; Russnes, Hege Elisabeth Giercksky & Naume, Bjørn (2017). Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up. Breast Cancer Research.  ISSN 1465-5411.  19(120) . doi: 10.1186/s13058-017-0911-9 Full text in Research Archive.
• Quigley, David; Tahiri, Andliena; Luders, Torben; Riis, Margit; Balmain, Allan; Børresen-Dale, Anne-Lise; Bukholm, Ida Rashida Khan & Kristensen, Vessela N. (2017). Age, estrogen, and immune response in breast adenocarcinoma and adjacent normal tissue. Oncoimmunology.  ISSN 2162-4011.  6(11) . doi: 10.1080/2162402X.2017.1356142 Full text in Research Archive. Show summary

  Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. There is a complex relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors. While low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. To characterize the impact of these factors on tumors and the tumor microenvironment, we measured gene expression in 195 breast adenocarcinomas and matched adjacent normal breast tissue samples collected at Akershus University Hospital (AHUS). Age and Body Mass Index (BMI) were independently associated with inflammation in adjacent normal tissue but not tumors. Estrogen Receptor (ER)-negative tumors had elevated macrophage expression compared with matched normal tissue, but ER-positive tumors showed an unexpected decrease in macrophage expression. We found an inverse relationship between the increase in tumor estrogen pathway expression compared with adjacent normal tissue and tumor macrophage score. We validated this finding in 126 breast tumor-normal pairs from the previously published METABRIC cohort. We developed a novel statistic, the Rewiring Coefficient, to quantify the rewiring of gene co-expression networks at the level of individual genes. Differential correlation analysis demonstrated distinct pathways were rewired during tumorigenesis. Our data support an immune suppressive effect of high doses of estrogen signaling in breast tumor microenvironment, suggesting that this effect contributes to the greater presence of prognostic and therapeutically relevant immune cells in ER-negative tumors.

• Shimelis, Hermela; Mesman, Romy L.S.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne M.G.R.; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M.; Aittomäki, Kristiina; Andrulis, Irene; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brouwers, Barbara; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ching-Yu; Choi, Ji-Yeob; Collée, Johanna Margriet; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hartman, Mikael; Hogervorst, Frans B.; Hollestelle, Antoinette; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela N.; Lai, Kah-Nyin; Lambrechts, Diether; Le Marchand, Loic; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Machackova, Eva; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; Miao, Hui; Michailidou, Kyriaki; Milne, Roger L.; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Olson, Janet E.; Olswold, Curtis; Oosterwijk, Jan J.C.; Osorio, Ana; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D.P.; Pylkäs, Katri; Radice, Paolo; Rashid, Muhammad Usman; Rhenius, Valerie; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schoemaker, Minouk J.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shrubsole, Martha; Shu, Xiao-Ou; Slager, Susan; Southey, Melissa C.; Stram, Daniel O.; Swerdlow, Anthony; Teo, Soo Hwang; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Van Asperen, Christi J.; Van Der Kolk, Lizet E.; Wang, Qin; Winqvist, Robert; Wu, Anna H.; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Leary, Jennifer; Walker, Logan; Foretova, Lenka; Fostira, Florentia; Claes, Kathleen B.M.; Varesco, Liliana; Moghadasi, Setareh; Easton, Douglas F.; Spurdle, Amanda; Devilee, Peter; Vrieling, Harry; Monteiro, Alvaro N.A.; Goldgar, David E.; Carreira, Aura; Vreeswijk, Maaike P.G. & Couch, Fergus J. (2017). BRCA2 hypomorphic missense variants confer moderate risks of breast cancer. Cancer Research.  ISSN 0008-5472.  77(11), s 2789- 2799 . doi: 10.1158/0008-5472.CAN-16-2568
• Silwal-Pandit, Laxmi; Nord, Silje; Gythfeldt, Hedda; Møller, Elen Kristine; Fleischer, Thomas; Rødland, Einar Andreas; Krohn, Marit; Borgen, Elin; Garred, Øystein; Olsen, Tone; Vu, Phuong Ngoc Thi; Skjerven, Helle; Fangberget, Anne; Holmen, Marit Muri; Schlichting, Ellen; Wille, Elisabeth; Stokke, Mette Norberg; Vollan, Hans Kristian Moen; Kristensen, Vessela N.; Langerød, Anita; Lundgren, Steinar; Wist, Erik; Naume, Bjørn; Lingjærde, Ole Christian; Børresen-Dale, Anne-Lise & Engebråten, Olav (2017). The longitudinal transcriptional response to neoadjuvant chemotherapy with and without bevacizumab in breast cancer. Clinical Cancer Research.  ISSN 1078-0432.  23(16), s 4662- 4670 . doi: 10.1158/1078-0432.CCR-17-0160 Full text in Research Archive.
• Bjaanæs, Maria Moksnes; Fleischer, Thomas; Halvorsen, Ann Rita; Daunay, Antoine; Busato, Florence; Solberg, Steinar; Jørgensen, Lars Hilmar; Kure, Elin H.; Edvardsen, Hege; Børresen-Dale, Anne-Lise; Brustugun, Odd Terje; Tost, Jörg; Kristensen, Vessela N. & Helland, Åslaug (2016). Genome-wide DNA methylation analyses in lung adenocarcinomas: Association with EGFR, KRAS and TP53 mutation status, gene expression and prognosis. Molecular Oncology.  ISSN 1574-7891.  10(2), s 330- 343 . doi: 10.1016/j.molonc.2015.10.021
• Cheng, Timothy H.T.; Thompson, Deborah J.; O'Mara, Tracy A.; Painter, Jodie N.; Glubb, Dylan M.; Flach, Susanne; Lewis, Annabelle; French, Juliet D.; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; MWebb, Penelope; Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Henders, Anjali K.; Martin, Nicholas G.; Montgomery, Grant W.; Nyholt, Dale R.; Ahmed, Shahana; Healey, Catherine S.; Shah, Mitul; Dennis, Joe; Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander; Ekici, Arif B.; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Durst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C.; Goode, Ellen L.; Fridley, Brooke L.; Winham, Stacey J.; Njølstad, Tormund Salvesen; Salvesen, Helga; Trovik, Jone; Werner, Henrica Maria Johanna; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Li, Mulin Jun; Yip, Shun H.; Wang, Junwen; KBolla, Manjeet; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P.; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L.; Peto, Julian; Swerdlow, Anthony J.; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J.; Giles, Graham G.; Kristensen, Vessela N.; Cox, Angela; MCunningham, Julie; Pharoah, Paul D.P.; Dunning, Alison M.; Edwards, Stacey L.; Easton, Douglas F.; Tomlinson, Ian & Spurdle, Amanda B. (2016). Five endometrial cancer risk loci identified through genome-wide association analysis. Nature Genetics.  ISSN 1061-4036.  48(6), s 667- 674 . doi: 10.1038/ng.3562 Show summary

  We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

• Couch, Fergus J.; Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A.; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Barile, Monica; Barkardottir, Rosa; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W.; Benitez, Javier; Blank, Stephanie V.; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J.; Chung, Wendy K.; Claes, Kathleen B.M.; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Darabi, Hatef; De La Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C.; Dolcetti, Riccardo; Domchek, Susan M.; Dorfling, Cecilia M.; Dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M; Eccles, Diana M; Ehrencrona, Hans; Ekici, Arif B; Eliassen, Heather; Ellis, Steve; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Gaudet, Mia M; Gayther, Simon A; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; Gonzalez-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guenel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E; Herzog, Josef; Hogervorst, Frans B L; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Humphreys, Keith; Hunter, David J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G; Knight, Julia A; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N.; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L; Makalic, Enes; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W M; Mcguffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M; Muranen, Taru A; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nordestgaard, Børge G; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Osorio, Ana; Park, Sue K; Peeters, Petra H; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J; Sanchez, Maria-Jose; Santella, Regina M; Sawyer, Elinor J; Schmidt, Daniel F; Schmidt, Marjanka K; Schmutzler, Rita K; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary B; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giske; Van Deurzen, Carolien H M; Van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D P; Monteiro, Alvaro A N; Garcia-Closas, Montserrat; Easton, Douglas F & Antoniou, Antonis C. (2016). Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nature Communications.  ISSN 2041-1723.  7:11375 . doi: 10.1038/ncomms11375 Full text in Research Archive.
• Darabi, Hatef; Beesley, Jonathan; Droit, Arnaud; Kar, Siddhartha; Nord, Silje; Marjaneh, Mahdi Moradi; Soucy, Penny; Michailidou, Kyriaki; Ghoussaini, Maya; Wahl, Hanna Fues; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Alonso, M Rosario; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Choi, Ji-Yeob; Conroy, Don M.; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Devilee, Peter; Dörk, Thilo; Easton, Douglas F.; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Goldberg, Mark S.; Gonzalez-Neira, Anna; Guénel, Pascal; Haiman, Christopher A.; Hallberg, Emily; Hamann, Ute; Hartman, Mikael; Hollestelle, Antoinette; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Johnson, Nichola; Kang, Daehee; Khan, Sofia; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela N.; Le Marchand, Loic; Lee, Soo Chin; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Mayes, Rebecca; McKay, James; Meindl, Alfons; Milne, Roger L.; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Olswold, Curtis; Orr, Nick; Peterlongo, Paolo; Pita, Guillermo; Pylkäs, Katri; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Southey, Melissa C.; Stram, Daniel O.; Surowy, Harald; Swerdlow, Anthony; Teo, Soo H.; Tessier, Daniel C.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine M.; Vincent, Daniel; Winqvist, Robert; Wu, Anna H.; Wu, Pei-Ei; Yip, Cheng Har; Zheng, Wei; Pharoah, Paul D.P.; Hall, Per; Edwards, Stacey L.; Simard, Jacques; French, Juliet D.; Chenevix-Trench, Georgia & Dunning, Alison M. (2016). Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs). Scientific Reports.  ISSN 2045-2322.  6 . doi: 10.1038/srep32512 Show summary

  Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.

• Demeulemeester, Jonas; Kumar, Parveen; Møller, Elen Kristine; Nord, Silje; Wedge, David C.; Peterson, April; Mathiesen, Randi Margit Ruud; Fjelldal, Renathe; Zamani Esteki, Masoud; Theunis, Koen; Fernandez Gallardo, Elia; Grundstad, A. Jason; Borgen, Elin; Baumbusch, Lars Oliver; Børresen-Dale, Anne-Lise; White, Kevin P.; Kristensen, Vessela N.; Van Loo, Peter; Voet, Thierry & Naume, Bjørn (2016). Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing. Genome Biology.  ISSN 1465-6906.  17(1) . doi: 10.1186/s13059-016-1109-7
• Dominguez Valentin, Mev; Gras Navarro, Andrea; Rahman, Mohummad Aminur; Kumar, Surendra; Retière, Christèle; Ulvestad, Elling; Kristensen, Vessela N.; Lund-Johansen, Morten; Lie, Benedicte Alexandra; Enger, Per Øyvind; Njølstad, Gro; Kristoffersen, Einar Klæboe; Lie, Stein Atle & Chekenya, Martha (2016). Identification of a natural killer cell receptor allele that prolongs survival of cytomegalovirus-positive glioblastoma patients. Cancer Research.  ISSN 0008-5472.  76(18), s 5326- 5336 . doi: 10.1158/0008-5472.CAN-16-1162
• Dunning, Alison M.; Michailidou, Kyriaki; Kuchenbaecker, Karoline B.; Thompson, Deborah; French, Juliet D.; Beesley, Jonathan; Healey, Catherine S.; Kar, Siddhartha; Pooley, Karen A.; Lopez-Knowles, Elena; Dicks, Ed; Barrowdale, Daniel; Sinnott-Armstrong, Nicholas A; Sallari, Richard C; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mahdi Moradi; Lee, Jason S.; Hills, Margaret; Jarosz, Monika; Drury, Suzie; Canisius, Sander; KBolla, Manjeet; Dennis, Joe; Wang, Qin; LHopper, John; Southey, Melissa C.; Broeks, Annegien; Schmidt, Marjanka K.; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W.; Fasching, Peter A.; Dos-Santos-Silva, Isabel; Peto, Julian; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guenel, Pascal; Truong, Therse; Bojesen, Stig E.; Flyger, Henrik; Gonzlez-Neira, Anna; Perez, Jose I.A.; Anton-Culver, Hoda; Eunjung, Lee; Arndt, Volker; Brenner, Hermann; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Aittomki, Kristiina; Blomqvist, Carl; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natasha; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-Chen; Wu, Anna H.; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Henderson, Brian E.; Goldberg, Mark S.; Teo, Soo H.; Yip, Cheng Har; Nordgard, Silje H.; Børresen-Dale, Anne-Lise; Kristensen, Vessela N.; Long, Jirong; Zheng, Wei; Pylks, Katri; Winqvist, Robert; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; Figueroa, Jonine; Sherman, Mark E.; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Van Den Ouweland, Ans M.W.; Humphreys, Keith; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Blot, William; Cai, Qiuyin; Ghoussaini, Maya; Perkins, Barbara J.; Shah, Mitul; Choi, Ji-Yeob; Kang, Daehee; Lee, Soo Chin; Hartman, Mikael; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Brennan, Paul; Sangrajrang, Suleeporn; Ambrosone, Christine B; Toland, Amanda E; Shen, Chen-Yang; Wu, Pei-Ei; Orr, Nick; Swerdlow, Anthony; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Kapuscinski, Miroslav; John, Esther M; Terry, Mary Beth; Daly, Mary B; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; Van Rensburg, Elizabeth J; Neuhausen, Susan L; Ejlertsen, Bent; Hansen, Thomas V.O.; Osorio, Ana; Benitez, Javier; Rando, Rachel; Weitzel, Jeffrey N; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Papi, Laura; Ottini, Laura; Konstantopoulou, Irene; Apostolou, Paraskevi; Garber, Judy; Rashid, Muhammad Usman; Frost, Debra; Izatt, Louise; Ellis, Steve; Godwin, Andrew K; Arnold, Norbert; Niederacher, Dieter; Rhiem, Kerstin; Bogdanova-Markov, Nadja; Sagne, Charlotte; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Sinilnikova, Olga M; Mazoyer, Sylvie; Isaacs, Claudine; MClaes, Kathleen B; De Leeneer, Kim; De La Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Khan, Sofia; Mensenkamp, Arjen R; Hooning, Maartje J; Rookus, Matti A; Kwong, Ava; Olah, Edith; Diez, Orland; Brunet, Joan; Pujana, Miquel Angel; Gronwald, Jacek; Huzarski, Tomasz; Barkardottir, Rosa B; Laframboise, Rachel; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Kyung Park, Sue; Lindor, Noralane; Couch, Fergus J; Tischkowitz, Marc; Foretova, Lenka; Vijai, Joseph; Offit, Kenneth; Singer, Christian F; Rappaport, Christine; MPhelan, Catherine; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Imyanitov, Evgeny N; Hulick, Peter J; Phillips, Kelly-Anne; Piedmonte, Marion; Mulligan, Anna Marie; Glendon, Gord; Bojesen, Anders; Thomassen, Mads; Caligo, Maria A; Yoon, Sook-Yee; Friedman, Eitan; Laitman, Yael; Borg, Ake; Von Wachenfeldt, Anna; Ehrencrona, Hans; Rantala, Johanna; Olopade, Olufunmilayo I; Ganz, Patricia A; Nussbaum, Robert L; Gayther, Simon A; LNathanson, Katherine; Domchek, Susan M; Arun, Banu K; Mitchell, Gillian; Karlan, Beth Y; Lester, Jenny; Maskarinec, Gertraud; Woolcott, Christy; Scott, Christopher; Stone, Jennifer; Apicella, Carmel; Tamimi, Rulla; Luben, Robert; Khaw, Kay-Tee; Helland, Åslaug; Haakensen, Vilde Drageset; Dowsett, Mitch; Pharoah, Paul DP; Simard, Jacques; Hall, Per; Garca-Closas, Montserrat; Vachon, Celine; Chenevix-Trench, Georgia; Antoniou, Antonis C; Easton, Douglas F & Edwards, Stacey L (2016). Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature Genetics.  ISSN 1061-4036.  48(4), s 374- 386 . doi: 10.1038/ng.3521 Show summary

  We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER−) and human ERBB2 (HER2+ or HER2−) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER− tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression

• Easton, Douglas F; Lesueur, Fabienne; Decker, Brennan; Michailidou, Kyriaki; Li, Jun; Allen, Jamie; Luccarini, Craig; Pooley, Karen A.; Shah, Mitul; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Ahmad, Jamil; Thompson, Ella R.; Damiola, Francesca; Pertesi, Maroulio; Voegele, Catherine; Mebirouk, Noura; Robinot, Nivonirina; Durand, Geoffroy; Forey, Nathalie; Luben, Robert N.; Ahmed, Shahana; Aittomäki, Kristiina; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Beckman, Matthias W.; Benitez, Javier; Van Den Berg, David; Blot, William J.; Bogdanova, Natalia V; Bojesen, Stig E.; Brenner, Hermann; Chang-Claude, Jenny; Chia, Kee Seng; Choi, Ji-Yeob; Conroy, Don M.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; Fostira, Florentia; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Gonzalez-Neira, Anna; Guenel, Pascal; Haiman, Christopher A.; Hall, Per; Hart, Steven N; Hartman, Mikael; Hooning, Maartje J.; Hsiung, Chia-Ni; Ito, Hidemi; Jakubowska, Anna; James, Paul A.; John, Esther M.; Johnson, Nichola; Jones, Michael; Kabisch, Maria; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela N.; Lambrechts, Diether; Li, Na; Myöhänen, Eija; Kemiläinen, Helena; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Meindl, Alfons; Mitchell, Gillian; Muir, Kenneth; Nevelsteen, Ines; Van Den Ouweland, Ans; Peterlongo, Paolo; Phuah, Sze Yee; Pylkäs, Katri; Rowley, Simone M; Sangrajrang, Suleeporn; Schmutzler, Rita K; Shen, Chen-Yang; Shu, Xiao-Ou; Southey, Melissa C; Surowy, Harald; Swerdlow, Anthony; Teo, Soo H; Tollenaar, Rob AEM; Tomlinson, Ian; Torres, Diana; Truong, Therese; Vachon, Celine; Verhoef, Senno; Wong-Brown, Michelle; Zheng, Wei; Zheng, Ying; Nevanlinna, Heli; Scott, Rodney J.; Andrulis, Irene L.; Wu, Anna H.; Hopper, John L.; Couch, Fergus J.; Winqvist, Robert; Burwinkel, Barbara; Sawyer, Elinor J.; Schmidt, Marjanka K.; Rudolph, Anja; Dörk, Thilo; Brauch, Hiltrud; Hamann, Ute; Neuhausen, Susan L.; Milne, Roger L.; Fletcher, Olivia; Pharoah, Paul D.P.; Campbell, Ian G.; Dunning, Alison M.; Le Calvez-Kelm, Florence; Goldgar, David E.; Tavtigian, Sean V.; Chenevix-Trench, Georgia; Kleivi, Kristine; Sauer, Torill; Riis, Margit; Grenaker, Grethe Irene; Bukholm, Ida Rashida Khan; Kiserud, Cecilie E.; Nord, Silje; Lønning, Per Eystein; Helland, Åslaug; Reinertsen, Kristin Valborg; Naume, Bjørn; Haakensen, Vilde Drageset; Ottestad, Lars; Kåresen, Rolf; Holmen, Marit Muri; Engebråten, Olav; Langerød, Anita & Schlichting, Ellen (2016). No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: Implications for gene panel testing. Journal of Medical Genetics.  ISSN 0022-2593.  53(5), s 298- 309 . doi: 10.1136/jmedgenet-2015-103529
• Eftang, Lars Lohne; Klajic, Jovana; Kristensen, Vessela N.; Tost, Jörg; Esbensen, Qin Ying; Blom, Gustav Peter; Bukholm, Ida Rashida Khan & Bukholm, Geir (2016). GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer. BMC Cancer.  ISSN 1471-2407.  16 . doi: 10.1186/s12885-016-2247-8 Full text in Research Archive.
• Fleischer, Thomas; Klajic, Jovana; Aure, Miriam Ragle; Louhimo, Riku; Pladsen, Arne Valebjørg; Ottestad, Lars; Touleimat, Nizar; Laakso, Marko; Halvorsen, Ann Rita; Grenaker, Grethe Irene; Riis, Margit; Helland, Åslaug; Hautaniemi, Sampsa; Lønning, Per Eystein; Naume, Bjørn; Børresen-Dale, Anne-Lise; Tost, Jörg & Kristensen, Vessela N. (2016). DNA methylation signature (SAM40) identifies subgroups of the Luminal A breast cancer samples with distinct survival. OncoTarget.  ISSN 1949-2553.  8(1), s 1074- 1082 . doi: 10.18632/oncotarget.13718
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• Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Therese; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; Gonzalez-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H.; Ven Den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J.; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Marchand, Loic Le; Goldberg, Mark S.; Teo, Soo H.; Taib, Nur Aishah Mohd; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; Garcia-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W.M.; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Pail D.P.; Easton, Douglas F.; Chanock, Stephen J.; Dunning, Alison M. & Figueroa, Jonine D. (2016). Fine-mapping of the 1p11.2 breast cancer susceptibility locus. PLOS ONE.  ISSN 1932-6203.  11:e0160316(8) . doi: 10.1371/journal.pone.0160316
• Jaime A, Espinoza; Jabeen, Shakila; Batra, Richa; Papaleo, Elena; Haakensen, Vilde Drageset; Wielenga, Vera Timmermans; Talman, Maj-Lis Møller; Brünner, Nils; Børresen-Dale, Anne-Lise; Gromov, Pavel; Helland, Åslaug; Kristensen, Vessela N. & Gromova, Irina (2016). Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics. Oncoimmunology.  ISSN 2162-4011.  5(12) . doi: 10.1080/2162402X.2016.1248015
• Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, Zsofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J; Thompson, Deborah J.; ABCTB Investigators, .; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K; Gentry-Maharaj, Aleksandra; Whittemore, Alice S.; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H.; Lindblom, Annika; Swerdlow, Anthony; AOCS Study Group & Australian, .; APCB BioResource, .; Ziogas, Argyrios; Ekici, Arif B.; Burwinkel, Barbara; Karlan, Beth Y.; Nordestgaard, Børge G.; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B.; Høgdall, Claus K.; Teerlink, Craig; Kang, Daehee; Tessier, Daniel C.; Schaid, Daniel J.; Stram, Daniel O.; Cramer, Daniel W.; Neal, David E.; Eccles, Diana; Flesch-Janys, Dieter; Edwards, Digna R. Velez; Wokozorczyk, Dominika; Levine, Douglas A.; Yannoukakos, Drakoulis; Sawyer, Elinor J.; Bandera, Elisa V.; Poole, Elizabeth M.; Goode, Ellen L.; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C.; Wiklund, Fredrik; Giles, Graham G.; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A.; Darabi, Hatef; Salvesen, Helga; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L.; Benitez, Javier; Doherty, Jennifer A.; Permuth, Jennifer B.; Chang-Claude, Jenny; Donovan, Jenny L.; Dennis, Joe; Schildkraut, Joellen M.; Schleutker, Johanna; Hopper, John L.; Kupryjanczyk, Jolanta; Park, Jong Y.; Figueroa, Jonine; Clements, Judith A.; Knight, Julia A.; Peto, Julian; Cunningham, Julie M.; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H.; Herkommer, Kathleen; Khaw, Kay-Tee; kConFab Investigators, .; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B.; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; FitzGerald, Liesel M.; Cook, Linda S.; Cannon-Albright, Lisa; Hooning, Maartje J.; Pike, Malcolm C.; Bolla, Manjeet K.; Luedeke, Manuel; Teixeira, Manuel R.; Goodman, Marc T.; Schmidt, Marjanka K.; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W.; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C.; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A.T.; Hou, Ming-Feng; Schoemaker, Minouk J.; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D.; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M.; Broberg, Per; Fasching, Peter A.; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K.; Stephenson, Robert A.; MacInnis, Robert J.; Hoover, Robert N.; Winqvist, Robert; Ness, Roberta; Milne, Roger L.; Travis, Ruth C.; Benlloch, Sara; Olson, Sara H.; McDonnell, Shannon K.; Tworoger, Shelley S.; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N.; Bojesen, Stig E.; Gapstur, Susan M.; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L.J.; the GENICA Network, .; the PRACTICAL consortium, .; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J.; Edwards, Todd L.; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela N.; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J.; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L.; Berchuck, Andrew; Dunning, Alison M.; Simard, Jacques; Haiman, Christopher A.; Spurdle, Amanda; Sellers, Thomas A.; Hunter, David J.; Henderson, Brian E.; Kraft, Peter; Chanock, Stephen J.; Couch, Fergus J.; Hall, Per; Gayther, Simon A.; Easton, Douglas F.; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D.P. & Lambrechts, Diether (2016). Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types. Cancer Discovery.  ISSN 2159-8274.  6(9), s 1052- 1067 . doi: 10.1158/2159-8290.CD-15-1227 Show summary

  Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis.

• Kaveh, Fatemeh; Baumbusch, Lars Oliver; Nebdal, Daniel J.H.; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian; Edvardsen, Hege; Kristensen, Vessela N. & Solvang, Hiroko Kato (2016). A systematic comparison of copy number alterations in four types of female cancer. BMC Cancer.  ISSN 1471-2407.  16(913) . doi: 10.1186/s12885-016-2899-4
• Kleibl, Zdenek & Kristensen, Vessela N. (2016). Women at high risk of breast cancer: Molecular characteristics, clinical presentation and management. Breast.  ISSN 0960-9776.  28, s 136- 144 . doi: 10.1016/j.breast.2016.05.006 Show summary

  The presence of breast cancer in any first-degree female relative in general nearly doubles the risk for a proband and the risk gradually increases with the number of affected relatives. Current advances in molecular oncology and oncogenetics may enable the identification of high-risk individuals with breast-cancer predisposition. The best-known forms of hereditary breast cancer (HBC) are caused by mutations in the high-penetrance genes BRCA1 and BRCA2. Other genes, including PTEN, TP53, STK11/LKB1, CDH1, PALB2, CHEK2, ATM, MRE11, RAD50, NBS1, BRIP1, FANCA, FANCC, FANCM, RAD51, RAD51B, RAD51C, RAD51D, and XRCC2 have been described as high- or moderate-penetrance breast cancer-susceptibility genes. The majority of breast cancer-susceptibility genes code for tumor suppressor proteins that are involved in critical processes of DNA repair pathways. This is of particular importance for those women who, due to their increased risk of breast cancer, may be subjected to more frequent screening but due to their repair deficiency might be at the risk of developing radiation-induced malignancies. It has been proven that cancers arising from the most frequent BRCA1 gene mutation carriers differ significantly from the sporadic disease of age-matched controls in their histopathological appearances and molecular characteristics. The increased depth of mutation detection brought by next-generation sequencing and a better understanding of the mechanisms through which these mutations cause the disease will bring novel insights in terms of oncological prevention, diagnostics, and therapeutic options for HBC patients.

• Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan; Delgado, Melissa K.; Lee, Janet M.; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Bandera, Elisa V.; Barile, Monica; Barkardottir, Rosa; Barrowdale, Daniel; Beckmann, Matthias W.; Benitez, Javier; Berchuck, Andrew; Bisogna, Maria; Bjørge, Line; Blomqvist, Carl; Blot, William; Bogdanova, Natalia; Bojesen, Anders; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Bruinsma, Fiona; Brunet, Joan; Buhari, Shaik Ahmad; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S.; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Canniotto, Rikki; Chang-Claude, Jenny; Chiquette, Jocelyne; Choi, Ji-Yeob; Claes, Kathleen B.M.; Cook, Linda S.; Cox, Angela; Cramer, Daniel W.; Cross, Simon S.; Cybulski, Cezary; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Diez, Orland; Doherty, Jennifer A; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dumont, Martine; Ehrencrona, Hans; Ejlertsen, Bent; Ellis, Steve; Engel, Christoph; Lee, Eunjung; Evans, D Gareth; Fasching, Peter A; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foretova, Lenka; Fostira, Florentia; Foulkes, William D; Fridley, Brooke L; Friedman, Eitan; Frost, Debra; Gambino, Gaetana; Ganz, Patricia A; Garber, Judy; Garcia-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghoussaini, Maya; Giles, Graham G; Glasspool, Rosalind; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; Gonzalez-Neira, Anna; Goode, Ellen L; Goodman, Marc T; Greene, Mark H; Gronwald, Jacek; Guenel, Pascal; Haiman, Christopher A; Hall, Per; Hallberg, Emily; Hamann, Ute; Hansen, Thomas VO; Harrington, Patricia A; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Heitz, Florian; Herzog, Josef; Høgdall, Estrid; Høgdall, Claus K; Hogervorst, Frans BL; Hollestelle, Antoinette; Hopper, John L; Hulick, Peter J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jensen, Allan; John, Esther M; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Kapuscinski, Miroslav; Karlan, Beth Y; Khan, Sofia; Kiemeney, Lambertus A; Kjaer, Susanne Kruger; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N.; Kupryjanczyk, Jolanta; Kwong, Ava; De La Hoya, Miguel; Laitman, Yael; Le, Nhu; De Leeneer, Kim; Lester, Jenny; Levine, Douglas A; Li, Jingmei; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Loud, Jennifer T; Lu, Karen; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Massuger, Leon FAG; Matsuo, Keitaro; Mazoyer, Sylvie; McGuffog, Lesley; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Milne, Roger L; Montagna, Marco; Moysich, Kirsten B; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Nord, Silje; Nussbaum, Robert L; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; O'Malley, David; Orlow, Irene; Orr, Nick; Osorio, Ana; Park, Sue Kyung; Pearce, Celeste L; Pejovic, Tanja; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Poole, Elizabeth M; Pylkäs, Katri; Radice, Paolo; Rantala, Johanna; Rashid, Muhammad Usman; Rennert, Gad; Rhenius, Valerie; Rhiem, Kerstin; Risch, Harvey A; Rodriguez, Gus; Rossing, Mary Anne; Rudolph, Anja; Salvesen, Helga B; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schildkraut, Joellen M; Schmidt, Marjanka K; Schmutzler, Rita K; Sellers, Thomas A; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Sieh, Weiva; Singer, Christian F; Sinilnikova, Olga M; Slager, Susan; Song, Honglin; Soucy, Penny; Southey, Melissa C; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Sutter, Christian; Swerdlow, Anthony; Tchatchou, Sandrine; Teixeira, Manuel R; Teo, Soo H; Terry, Kathryn L; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; Toland, Amanda Ewart; Tomlinson, Ian; Torres, Diana; Truong, Therese; Tseng, Chiu-Chen; Tung, Nadine; Tworoger, Shelley S; Vachon, Celine; Van Den Ouweland, Ans MW; Van Doorn, Helena C; Van Rensburg, Elizabeth J; Van't Veer, Laura J; Vanderstichele, Adriaan; Vergote, Ignace; Vijai, Joseph; Wang, Qin; Wang-Gohrke, Shan; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wildiers, Hans; Winqvist, Robert; Wu, Anna H; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Khanna, Kum Kum; Simard, Jacques; Monteiro, Alvaro N; French, Juliet D; Couch, Fergus J; Freedman, Matthew L; Easton, Douglas F; Dunning, Alison M; Pharoah, Paul D; Edwards, Stacey L; Chenevix-Trench, Georgia; Antoniou, Antonis C & Gayther, Simon A. (2016). Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nature Communications.  ISSN 2041-1723.  7:12675 . doi: 10.1038/ncomms12675
• Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B.; Behrens, Sabine; Goode, Ellen L.; Bolla, Manjeet K.; Dennis, Joe; Dunning, Alison M.; Easton, Douglas F.; Wang, Qin; Benitez, Javier; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Fasching, Peter A.; Haeberle, Lothar; Peto, Julian; Dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guenel, Pascal; Truong, Therese; Bojesen, Stig E.; Flyger, Henrik; Nielsen, Sune F.; Nordestgaard, Børge G.; Gonzalez-Neira, Anna; Menendez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Fagerholm, Rainer; Dörk, Thilo; Bogdanova, Natalia V.; Mannermaa, Arto; Hartikainen, Jaana M.; van Dijck, Laurien; Smeets, Ann; Flesch-Janys, Dieter; Eilber, Ursula; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J.; Hallberg, Emily; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Schumacher, Fredrick; Simard, Jacques; Goldberg, Mark S.; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Winqvist, Robert; Grip, Mervi; Andrulis, Irene L.; Glendon, Gord; Garcia-Closas, Montserrat; Figueroa, Jonine; Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei; Cox, Angela; Cross, Simon S.; Pharoah, Paul D.P.; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Ademuyiwa, Foluso; Ambrosone, Christine B.; Swerdlow, Anthony; Jones, Michael & Chang-Claude, Jenny (2016). Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. Human Genetics.  ISSN 0340-6717.  135(1), s 137- 154 . doi: 10.1007/s00439-015-1616-8
• Lesurf, Robert; Aure, Miriam Ragle; Mørk, Hanne Håberg; Vitelli, Valeria; Lundgren, Steinar; Børresen-Dale, Anne-Lise; Kristensen, Vessela N.; Wärnberg, Fredrik; Hallett, Michael & Sørlie, Therese (2016). Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer. Cell reports.  ISSN 2211-1247.  16(4), s 1166- 1179 . doi: 10.1016/j.celrep.2016.06.051 Full text in Research Archive.
• Liang, Dong; Hildebrant, Michelle A T; Ness, Roberta B; Modugno, Francesmary; Pearce, Leigh; Goodman, Marc T; Thompson, Pamela J; Brenner, Hermann; Butterbach, Katja; Meindl, Alfons; Hahnen, Eric; Wappenschmidt, Barbara; Brauch, Hiltrud; Bruning, Thomas; Blomqvist, Carl; Khan, Sofia; Nevanlinna, Heli; Pelttari, Liisa M; Aittomäki, Kristiina; Butzow, Ralf; Bogdanova, Natalia V; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Rantala, Johanna; Kosma, Veli-Matti; Mannermaa, Arto; Lambrechts, Diether; Neven, Patrick; Claes, Kathleen B M; Van Maerken, Tom; Chang-Claude, Jenny; Flesch-Janys, Diether; Heitz, Florian; Varon-Mateeva, Raymonda; Peterlongo, Paolo; Radice, Paolo; Viel, Alessandra; Barile, Monica; Peissel, Bernard; Manoukian, Siranoush; Montagna, Marco; Oliani, Cristina; Peixoto, Ana; Teixeira, Manuel R; Collavoli, Anita; Hallberg, Emily; Olson, Janet E; Goode, Ellen L; Hart, Steven N; Shimelis, Hermela; Cunningham, Julie M; Giles, Graham G; Milne, Roger L; Healey, Sue; Tucker, Kathy; Haiman, Christopher A; Henderson, Brian E; Goldberg, Mark S; Tischkowitz, Marc; Simard, Jacques; Soucy, Penny; Eccles, Diana M.; Le, Nhu; Børresen-Dale, Anne-Lise; Kristensen, Vessela N.; Salvesen, Helga; Bjørge, Line; Bandera, Elisa V; Goldgar, David E; Brunet, Joan; Anton-Culver, Hoda; Eunjung, Lee; John, Esther M; Neuhausen, Susan L; Ding, Yuan Chun; Castillo, Danielle; Weitzel, Jeffrey N; Ganz, Patricia A; Nussbaum, Robert L; Chan, Salina B; Karlan, Beth Y; Lester, Jenny; Wu, Anna; Gayther, Simon; Ramus, Susan J; Sieh, Weiva; Whittermore, Alice S; Monteiro, Alvaro NA; Phelan, Catherine M; Terry, Mary Beth; Piedmonte, Marion; Offit, Kenneth; Robson, Mark; Levine, Douglas; Moysich, Kirsten B; Cannioto, Rikki; Olson, Sara H; Daly, Mary B; Nathanson, Katherine L; Domchek, Susan M; Lu, Karen H; Hildebrant, Michelle AT; Ness, Roberta; Aittomaki, Kristiina; Dork, Thilo; Claes, Kathleen BM; Flesch-Janys, Dieter; Eccles, Diana M; Borresen-Dale, Anne-Lise; Kristensen, Vessela; Salvesen, Helga B; Bjorge, Line; Risch, Harvey; Zheng, Wei; Beeghly-Fadiel, Alicia; Cai, Hui; Pylkas, Katri; Tollenaar, Robert AEM; Ouweland, Ans MW Van Der; Andrulis, Irene L; Knight, Julia A; Narod, Steven; Devilee, Peter; Winqvist, Robert; Figueroa, Jonine; Greene, Mark H; Mai, Phuong L; Loud, Jennifer T; Garcia-Closas, Montserrat; Schoemaker, Minouk J; Czene, Kamila; Darabi, Hatef; McNeish, Iain; Siddiquil, Nadeem; Glasspool, Rosalind; Kwong, Ava; Park, Sue K; Teo, Soo Hwang; Yoon, Sook-Yee; Matsuo, Keitaro; Hosono, Satoyo; Woo, Yin Ling; Gao, Yu-Tang; Foretova, Lenka; Singer, Christian F; Rappaport-Feurhauser, Christine; Friedman, Eitan; Laitman, Yael; Rennert, Gad; Imyanitov, Evgeny N; Hulick, Peter J; Olopade, Olufunmilayo I; Senter, Leigha; Olah, Edith; Doherty, Jennifer A; Schildkraut, Joellen; Koppert, Linetta B; Kiemeney, Lambertus A; Massuger, Leon FAG; Cook, Linda S; Pejovic, Tanja; Li, Jingmei; Borg, Ake; Ofverholm, Anna; Rossing, Mary Anne; Wentzensen, Nicolas; Henriksson, Karin; Cox, Angela; Cross, Simon S; Pasini, Barbara J; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Agnarsson, Bjarni A; Kupryjanczyk, Jolanta; Moes-Sosnowska, Joanna; Fostira, Florentia; Konstantopoulou, Irene; Slager, Susan; Jones, Michael; Antoniou, Antonis C; Berchuck, Andrew; Swerdlow, Anthony; Chenevix-Trench, Georgia; Dunning, Alison M; Pharoah, Paul DP; Hall, Per; Easton, Douglas F; Couch, Fergus J & Spurdle, Amanda B (2016). BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers. Journal of the National Cancer Institute.  ISSN 0027-8874.  108(2), s 1- 10 . doi: 10.1093/jnci/djv315 Show summary

  Background: The K3326X variant in BRCA2 ( BRCA2 *c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (OR w ) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (OR w = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10 -6 ) and invasive ovarian cancer (OR w = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10 -3 ). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (OR w = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10 -5 and OR w = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10 -5 , respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

• Liu, Jingjing; Lončar, Ivona; Collée, J. Margriet; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Andrulis, Irene L.; Barile, Monica; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Blomqvist, Carl; Boeckx, Bram; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Chen, Shou-Tung; Chenevix-Trench, Georgia; Cheng, Ching Y.; Choi, Ji-Yeob; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Cuk, Katarina; Czene, Kamila; Dörk, Thilo; Dos-Santos-Silva, Isabel; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Goldberg, Mark S.; González-Neira, Anna; Guénel, Pascal; Haiman, Christopher A.; Hamann, Ute; Hart, Steven N.; Hartman, Mikael; Hatse, Sigrid; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Kabisch, Maria; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela N.; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Matsuo, Keitaro; Milne, Roger L.; Neuhausen, Susan L.; Nevanlinna, Heli; Orr, Nick; Pérez, Jose I.A.; Peto, Julian; Putti, Thomas Choudary; Pylkäs, Katri; Radice, Paolo; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schneeweiss, Andreas; Shen, Chen-Yang; Shrubsole, Martha J.; Shu, Xiao-Ou; Simard, Jacques; Southey, Melissa C.; Swerdlow, Anthony; Teo, Soo H.; Tessier, Daniel C.; Thanasitthichai, Somchai; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Vachon, Celine; Winqvist, Robert; Wu, Anna H.; Yannoukakos, Drakoulis; Zheng, Wei; Hall, Per; Dunning, Alison M.; Easton, Douglas F.; Hooning, Maartje J.; Van Den Ouweland, Ans M.W.; Martens, John W.M. & Hollestelle, Antoinette (2016). Rs2735383, located at a microRNA binding site in the 3'UTR of NBS1, is not associated with breast cancer risk. Scientific Reports.  ISSN 2045-2322.  6 . doi: 10.1038/srep36874 Show summary

  NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3′-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936–1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969–1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905–1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.

• Painter, Jodie N.; O'Mara, Tracy A.; Marquart, Louise; Webb, Penelope M.; Attia, John; Medland, Sarah E.; Cheng, Timothy; Dennis, Joe; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Ahmed, Shahana; Healey, Catherine S.; Shah, Mitul; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley V.; Beckmann, Matthias W.; Ekici, Arif B.; Fasching, Peter A.; Hein, Alexander; Rubner, Matthias; Czene, Kamila; Darabi, Hatef; Hall, Per; Li, Jingmei; Dörk, Thilo; Durst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B.; Amant, Frederic; Annibali, Daniela; Depreeuw, Jeroen; Lambrechts, Diether; Neven, Patrick; Cunningham, Julie M.; Dowdy, Sean C.; Goode, Ellen L.; Fridley, Brooke L.; Winham, Stacey J.; Njølstad, Tormund Salvesen; Salvesen, Helga; Trovik, Jone; Werner, Henrica Maria Johanna; Ashton, Katie A.; Otton, Geoffrey; Proietto, Anthony; Mints, Miriam; Tham, Emma; Bolla, Manjeet K.; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P.; Hopper, John L; Peto, Julian; Swerdlow, Anthony J.; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J.; Giles, Graham G; Kristensen, Vessela N.; Cox, Angela; Pharoah, Paul D.P.; Tomlinson, Ian; Dunning, Alison M.; Easton, Douglas F.; Thompson, Deborah J. & Spurdle, Amanda B. (2016). Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer. Cancer Epidemiology, Biomarkers and Prevention.  ISSN 1055-9965.  25(11), s 1503- 1510 . doi: 10.1158/1055-9965.EPI-16-0147 Show summary

  Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling.

• Pelttari, Liisa M.; Khan, Sofia; Vuorela, Mikko; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Schleutker, Johanna; Winqvist, Robert; Kallioniemi, Anne; Dörk, Thilo; Bogdanova, Natalia V.; Figueroa, Jonine; Pharoah, Paul D.P.; Schmidt, Marjanka K.; Dunning, Alison M.; García-Closas, Montserrat; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Hopper, John L.; Southey, Melissa C.; Rosenberg, Efraim H.; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Nordestgaard, Børge G.; Benitez, Javier; González-Neira, Anna; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Brüning, Thomas; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; kConFab/AOCS Investigators, .; Van Dyck, Laurien; Janssen, Hilde; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Hallberg, Emily; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Schumacher, Fredrick; Simard, Jacques; Dumont, Martine; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Grip, Mervi; Andrulis, Irene L.; Glendon, Gord; Devilee, Peter; Seynaeve, Caroline; Hooning, Maartje J.; Collée, Margriet; Cox, Angela; Cross, Simon S.; Shah, Mitul; Luben, Robert N.; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Couch, Fergus J.; Yannoukakos, Drakoulis; Orr, Nick; Swerdlow, Anthony; Darabi, Hatef; Li, Jingmei; Czene, Kamila; Hall, Per; Easton, Douglas F.; Mattson, Johanna; Blomqvist, Carl; Aittomäki, Kristiina & Nevanlinna, Heli (2016). RAD51B in familial breast cancer. PLOS ONE.  ISSN 1932-6203.  11(5) . doi: 10.1371/journal.pone.0153788 Show summary

  Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

• Petridis, Christos; Brook, Mark N.; Shah, Vandna; Kohut, Kelly; Gorman, Patricia; Caneppele, Michele; Levi, Dina; Papouli, Efterpi; Orr, Nick; Cox, Angela; Cross, Simon S.; dos-Santos-Silva, Isabel; Peto, Julian; Swerdlow, Anthony; Schoemaker, Minouk J.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Benitez, Javier; Gonzalez-Neira, Anna; Tessier, Daniel C.; Vincent, Daniel; Li, Jingmei; Figueroa, Jonine; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Soucy, Penny; Simard, Jacques; Milne, Roger L.; Giles, Graham G.; Margolin, Sara; Lindblom, Annika; Bruning, Thomas; Brauch, Hiltrud; Southey, Melissa C.; Hopper, John L.; Dörk, Thilo; Bogdanova, Natalia V.; Kabisch, Maria; Hamann, Ute; Schmutzler, Rita K.; Meindl, Alfons; Brenner, Hermann; Arndt, Volker; Winqvist, Robert; Pylkäs, Katri; Fasching, Peter A.; Beckmann, Matthias W.; Lubinski, Jan; Jakubowska, Anna; Mulligan, Anna Marie; Andrulis, Irene L.; Tollenaar, Rob A.E.M.; Devilee, Peter; Le Marchand, Loic; Haiman, Christopher A.; Mannermaa, Arto; Kosma, Veli-Matti; Radice, Paolo; Peterlongo, Paolo; Marme, Frederik; Burwinkel, Barbara; van Deurzen, Carolien H.M.; Hollestelle, Antoinette; Miller, Nicola; Kerin, Michael J.; Lambrechts, Diether; Floris, Giuseppe; Wesseling, Jelle; Flyger, Henrik; Bojesen, Stig E.; Yao, Song; Ambrosone, Christine B.; Chenevix-Trench, Georgia; Truong, Therese; Guenel, Pascal; Rudolph, Anja; Chang-Claude, Jenny; Nevanlinna, Heli; Blomqvist, Carl; Czene, Kamila; Brand, Judith S.; Olson, Janet E.; Couch, Fergus J.; Dunning, Alison M.; Hall, Per; Easton, Douglas F.; Pharoah, Paul D.P.; Pinder, Sarah E.; Schmidt, Marjanka K.; Tomlinson, Ian; Roylance, Rebecca; Garcia-Closas, Montserrat & Sawyer, Elinor J. (2016). Genetic predisposition to ductal carcinoma in situ of the breast. Breast Cancer Research.  ISSN 1465-5411.  18:22 . doi: 10.1186/s13058-016-0675-7 Show summary

  Background Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. Methods To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Results Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8. Conclusion In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.

• Sas-Chen, Aldema; Aure, Miriam Ragle; Leibovich, Limor; Carvalho, Silvia; Enuka, Yehoshua; Körner, Cindy; Polycarpou-Schwarz, Maria; Lavi, Sara; Nevo, Nava; Kuznetsov, Yuri; Yuan, Justin; Azuaje, Francisco; Ulitsky, Igor; Diederichs, Sven; Wiemann, Stefan; Yakhini, Zohar; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Yarden, Yosef; Sauer, Torill; Geisler, Jürgen; Hofvind, Solveig; Bathen, Tone Frost; Borgen, Elin; Engebråten, Olav; Fodstad, Øystein; Garred, Øystein; Geitvik, Gry; Kåresen, Rolf; Naume, Bjørn; Mælandsmo, Gunhild; Russnes, Hege Elisabeth Giercksky; Schlichting, Ellen; Sørlie, Therese; Lingjærde, Ole Christian; Sahlberg, Kristine Kleivi; Skjerven, Helle & Fritzman, Britt (2016). LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer. EMBO Molecular Medicine.  ISSN 1757-4676.  8(9), s 1052- 1064 . doi: 10.15252/emmm.201606198 Full text in Research Archive.
• Schmidt, Marjanka K.; Hogervorst, Frans; Van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; Van Den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Antoniou, Antonis C.; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V.; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Bruning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; Garcia-Closas, Montserrat; Giles, Graham G.; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L.; Jakubowska, Anna; John, Esther M.; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A.; Kosma, Veli-Matti; Kristensen, Vessela N.; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L.; Muranen, Taru A.; Newcomb, Polly A.; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D.P.; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C.; Spurdle, Amanda B.; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S.; Ziogas, Argyrios; Van Der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig & Easton, Douglas F. (2016). Age-And tumor subtype-specific breast cancer risk estimates for CHEK2∗1100delC Carriers. Journal of Clinical Oncology.  ISSN 0732-183X.  34(23), s 2750- 2760 . doi: 10.1200/JCO.2016.66.5844 Show summary

  Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. Patients and Methods CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Results Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10−20). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10−21]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10−4). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.

• Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei; Michailidou, Kyriaki; Ghoussaini, Maya; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Milne, Roger L.; Shu, Xiao-Ou; Beesley, Jonathan; Kar, Siddhartha; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Zhao, Zhiguo; Guo, Xingyi; Benitez, Javier; Beeghly-Fadiel, Alicia; Blot, William; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broeks, Annegien; Bruning, Thomas; Burwinkel, Barbara; Cai, Hui; Canisius, Sander; Chang-Claude, Jenny; Choi, Ji-Yeob; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Droit, Arnaud; Dork, Thilo; Fasching, Peter A.; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gaborieau, Valerie; Garcia-Closas, Montserrat; Giles, Graham G.; Grip, Mervi; Guenel, Pascal; Haiman, Christopher A.; Hamann, Ute; Hartman, Mikael; Miao, Hui; Hollestelle, Antoinette; Hopper, John L.; Hsiung, Chia-Ni; Ito, Hidemi; Jakubowska, Anna; Johnson, Nichola; Torres, Diana; Kabisch, Maria; Kang, Daehee; Khan, Sofia; Knight, Julia A.; Kosma, Veli-Matti; Lambrechts, Diether; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McLean, Catriona; Meindl, Alfons; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Nord, Silje; Børresen-Dale, Anne-Lise; Olson, Janet E.; Orr, Nick; Van Den Ouweland, Ans M.W.; Peterlongo, Paolo; Choudary Putti, Thomas; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Shen, Chen-Yang; Hou, Ming-Feng; Shrubsole, Martha J.; Southey, Melissa C.; Swerdlow, Anthony; Hwang Teo, Soo; Thienpont, Bernard; Toland, Amanda E.; Tollenaar, Robert A.E.M.; Tomlinson, Ian; Truong, Therese; Tseng, Chiu-Chen; Wen, Wanqing; Winqvist, Robert; Wu, Anna H.; Har Yip, Cheng; Zamora, Pilar M.; Zheng, Ying; Floris, Giuseppe; Cheng, Ching-Yu; Hooning, Maartje J.; Martens, John W.M.; Seynaeve, Caroline; Kristensen, Vessela N.; Hall, Per; Pharoah, Paul D.P.; Simard, Jacques; Chenevix-Trench, Georgia; Dunning, Alison M.; Antoniou, Antonis C.; Easton, Douglas F.; Cai, Qiuyin & Long, Jirong (2016). Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. International Journal of Cancer.  ISSN 0020-7136.  139(6), s 1303- 1317 . doi: 10.1002/ijc.30150
• Solvang, Hiroko Kato; Frigessi, Arnoldo; Kaveh, Fatemeh; Riis, Margit; Luders, Torben; Bukholm, Ida Rashida Khan; Kristensen, Vessela N. & Andreassen, Bettina Kulle (2016). Gene expression analysis supports tumor threshold over 2.0 cm for T-category breast cancer. EURASIP Journal on Bioinformatics and Systems Biology.  ISSN 1687-4145.  2016(6) . doi: 10.1186/s13637-015-0034-5 Full text in Research Archive.
• Southey, Melissa C; Goldgar, David E; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D; Dennis, Joe; Michailidou, Kyriaki; Van Rensburg, Elizabeth J; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L; Dörk, Thilo; Claes, Kathleen BM; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A; Dowty, James G; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nicola; Bolla, Manjeet K; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guenel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan; Ziogas, Argyrios; Clarke, Christina A.; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Spurdle, Amanda B; Wauters, Els; Smeets, Dominiek; Beuselinck, Benoit; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Olson, Janet E; Vachon, Celine; Pankratz, Vernon S.; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Marchand, Loic Le; Kristensen, Vessela N.; Alnæs, Grethe Irene Grenaker; Zheng, Wei; Hunter, David J; Lindstrom, Sara; Hankinson, Susan E; Kraft, Peter; Andrulis, Irene; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Jukkola-Vuorinen, Arja; Grip, Mervi; Kauppila, Saila; Devilee, Peter; Tollenaar, Robert AEM; Seynaeve, Caroline; Hollestelle, Antoinette; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Eccles, Diana M; Rafiq, Sajjad; Tapper, William J.; Gerty, Sue M; Hooning, Maartje J; Martens, John WM; Collee, J Margriet; Tilanus-Linthorst, Madeleine; Hall, Per; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Cox, Angela; Reed, Malcolm WR; Luccarini, Craig; Baynes, Caroline; Dunning, Alison M; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Simard, Jacques; Dumont, Martine; Soucy, Penny; Eeles, Rosalind; Muir, Kenneth; Wiklund, Fredrik; Gronberg, Henrik; Schleutker, Johanna; Nordestgaard, Børge G; Weischer, Maren; Travis, Ruth C; Neal, David; Donovan, Jenny L; Hamdy, Freddie C; Khaw, Kay-Tee; Stanford, Janet L.; Blot, William J.; Thibodeau, Stephen; Schaid, Daniel J.; Kelley, Joseph L; Maier, Christiane; Kibel, Adam S.; Cybulski, Cezary; Cannon-Albright, Lisa; Butterbach, Katja; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Renner, Stefan P; Hartmann, Arndt; Hein, Alexander; Ruebner, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambretchs, Sandrina; Doherty, Jennifer A; Rossing, Mary Anne; Nickels, Stefan; Eilber, Ursula; Wang-Gohrke, Shan; Odunsi, Kunle; Sucheston-Campbell, Lara E; Friel, Grace; Lurie, Galina; Killeen, Jeffrey L; Wilkens, Lynne R; Goodman, Marc T; Runnebaum, Ingo; Hillemanns, Peter A; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; Moysich, Kirsten B; Du Bois, Andreas; Heitz, Florian; Harter, Philipp; Kommoss, Stefan; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjaer, Susanne Kruger; Høgdall, Estrid; Peissel, Bernard; Bonanni, Bernardo; Bernard, Loris; Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Cunningham, Julie M; Larson, Melissa C; Fogarty, Zachary C; Kalli, Kimberly R; Liang, Dong; Lu, Karen H; Hildebrandt, Michelle AT; Wu, Xifeng; Levine, Douglas A; Dao, Fanny; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Marks, Jeffrey R; Akushevich, Lucy; Cramer, Daniel W; Schildkraut, Joellen; Terry, Kathryn L; Poole, Elizabeth M; Stampfer, Meir; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Bjørge, Line; Salvesen, Helga; van Altena, Anne M; Aben, Katja KH; Kiemeney, Lambertus A; Massuger, Leon FAG; Pejovic, Tanja; Bean, Yukie; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Gorski, Bohdan; Gronwald, Jacek; Menkiszak, Janusz; Høgdall, Claus K; Lundvall, Lene; Nedergaard, Lotte; Engelholm, Svend Aage; Dicks, Ed; Tyrer, Jonathan; Campbell, Ian; McNeish, Iain; Paul, James; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Cai, Hui; Shu, Xiao-Ou; Teten, Rachel T; Sutphen, Rebecca; McLaughlin, John R; Narod, Steven A; Phelan, Catherine M; Monteiro, Alvaro N; Fenstermacher, David; Lin, Hui-Yi; Permuth, Jennifer B; Sellers, Thomas A; Chen, Y Ann; Tsai, Ya-Yu; Chen, Zhihua; Gentry-Maharaj, Aleksandra; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Wu, Anna H; Pearce, Celeste L; Van Den Berg, David; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul DP; Song, Honglin; Winship, Ingrid; Chenevix-Trench, Georgia; Giles, Graham G; Tavtigian, Sean V.; Easton, Doug F. & Milne, Roger L (2016). PALB2, CHEK2 and ATM rare variants and cancer risk: Data from COGS. Journal of Medical Genetics.  ISSN 0022-2593.  53(12), s 800- 811 . doi: 10.1136/jmedgenet-2016-103839 Show summary

  Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

• Thienpont, Bernard; Steinbacher, Jessica; Zhao, Hui; D'Anna, Flora; Kuchnio, Anna; Ploumakis, Athanasios; Ghesquière, Bart; Van Dyck, Laurien; Boeckx, Bram; Schoonjans, Luc; Hermans, Els; Amant, Frederic; Kristensen, Vessela N.; Koh, Kian Peng; Mazzone, Massimiliano; Coleman, Mathew L.; Carell, Thomas; Carmeliet, Peter & Lambrechts, DIether (2016). Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature.  ISSN 0028-0836.  537(7618), s 63- 68 . doi: 10.1038/nature19081 Show summary

  Hypermethylation of the promoters of tumour suppressor genes represses transcription of these genes, conferring growth advantages to cancer cells. How these changes arise is poorly understood. Here we show that the activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumour hypoxia in human and mouse cells. TET enzymes catalyse DNA demethylation through 5-methylcytosine oxidation. This reduction in activity occurs independently of hypoxia-associated alterations in TET expression, proliferation, metabolism, hypoxia-inducible factor activity or reactive oxygen species, and depends directly on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro. In patients, tumour suppressor gene promoters are markedly more methylated in hypoxic tumour tissue, independent of proliferation, stromal cell infiltration and tumour characteristics. Our data suggest that up to half of hypermethylation events are due to hypoxia, with these events conferring a selective advantage. Accordingly, increased hypoxia in mouse breast tumours increases hypermethylation, while restoration of tumour oxygenation abrogates this effect. Tumour hypoxia therefore acts as a novel regulator of DNA methylation.

• Thompson, Deborah J.; O'Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Folkerd, Elizabeth; Doody, Deborah; Dennis, Joe; Webb, Penelope M.; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Michailidou, Kyriaki; Tyrer, Jonathan P.; Maranian, Mel J.; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif B.; Dörk, Thilo; Hillemanns, Peter; Durst, Matthias; Runnebaum, Ingo; Zhao, Hui; Depreeuw, Jeroen; Schrauwen, Stefanie; Amant, Frederic; Goode, Ellen L.; Fridley, Brooke L.; Dowdy, Sean C.; Winham, Stacey J.; Salvesen, Helga; Trovik, Jone; Njølstad, Tormund Salvesen; Werner, Henrica Maria Johanna; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Carvajal-Carmona, Luis; Tham, Emma; Liu, Tao; Mints, Miriam; Scott, Rodney J.; McEvoy, Mark; Attia, John; Holliday, Elizabeth G.; Montgomery, Grant W.; Martin, Nicholas G.; Nyholt, Dale R.; Henders, Anjali K.; Hopper, John L.; Traficante, Nadia; Ruebner, Matthias; Swerdlow, Anthony J.; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Lambrechts, Diether; Chang-Claude, Jenny; Couch, Fergus J.; Giles, Graham G.; Kristensen, Vessela N.; Cox, Angela; Bolla, Manjeet K.; Wang, Qin; Bojesen, Stig E.; Shah, Mitul; Luben, Robert; Khaw, Kay-Tee; Pharoah, Paul D.P.; Dunning, Alison M.; Tomlinson, Ian; Dowsett, Mitch; Easton, Douglas F. & Spurdle, Amanda B. (2016). CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer. Endocrine-Related Cancer.  ISSN 1351-0088.  23(2), s 77- 91 . doi: 10.1530/ERC-15-0386
• Tinholt, Mari; Sandset, Per Morten; Mowinckel, Marie-Christine; Garred, Øystein; Sahlberg, Kristine Kleivi; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Jacobsen, Anne Flem; Skretting, Grethe & Iversen, Nina (2016). Determinants of acquired activated protein C resistance and D-dimer in breast cancer. Thrombosis Research.  ISSN 0049-3848.  145, s 78- 83 . doi: 10.1016/j.thromres.2016.08.003
• Wyszynski, Asaf; Hong, Chi-Chen; Lam, Kristin; Michailidou, Kyriaki; Lytle, Christian; Yao, Song; Zhang, Yali; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Nordestgaard, Børge G; González-Neira, Anna; Benitez, Javier; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; Van Den Berg, David; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J; Olson, Janet E; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Henderson, Brian E; Dumont, Martine; Teo, Soo Hwang; Wong, Tien Y; Kristensen, Vessela N.; Zheng, Wei; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Figueroa, Jonine; Klevebring, Daniel; Czene, Kamila; Hooning, Maartje J; van den Ouweland, Ans MW; Darabi, Hatef; Shu, Xiao-Ou; Gao, Yu-Tang; Cox, Angela; Blot, William; Signorello, Lisa B; Shah, Mitul; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Miao, Hui; Hamann, Ute; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; McKay, James; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Pharoah, Paul DP; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Bandera, Elisa; Amos, Chris; Ambrosone, Christine; Easton, Douglas F & Cole, Michael D (2016). An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Human Molecular Genetics.  ISSN 0964-6906.  25(17), s 3863- 3876 . doi: 10.1093/hmg/ddw223 Show summary

  Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55–0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10−19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10−15 − 5.6 × 10−17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

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• Bahrami, Nazli; Jabeen, Shakila; Sauer, Torill; Kristensen, Vessela N.; Gundersen, Joanna M. & Geisler, Jürgen (2019). The aromatase inactivator exemestane suppresses serum leptin levels significantly in vivo - in contrast to the aromatase inhibitor letrozole.
• Tinholt, Mari; Stavik, Benedicte; Sletten, Marit; Garred, Øystein; Tekpli, Xavier; Kristensen, Vessela N.; Sahlberg, Kristine Kleivi; Sandset, Per Morten & Iversen, Nina (2019). Coagulation factor V is associated with immune response and tumor lymphocyte recruitment in breast cancer.
• Vaske, Charlie; Parulkar, R.; Bahrami, Nazli; Sauer, Torill; Lüders, Torben; Lorentzen, Annika; Gravdehaug, Berit; Kristensen, Vessela N. & Geisler, Jürgen (2019). Time-course DNA and RNA profiling reveals down-regulation of all members of the sulfotransferase 1A subfamily during neoadjuvant therapy with aromatase inhibitors.
• Bahrami, Nazli; Sauer, Torill; Loeng, Marie; Gravdehaug, Berit; Engebretsen, Siri; Aljabri, Belal; Bemanian, Vahid; Lindstrøm, Jonas Christoffer; Luders, Torben; Kristensen, Vessela N. & Geisler, Jürgen (2018). The NEO-LET-EXE trial: an intra-patient cross-over study to explore the lack of cross-resistance between steroidal and nonsteroidal aromatase inhibitors.
• Jabeen, Shakila & Kristensen, Vessela N. (2018). Non-invasive biomarkers of metabolic and immune profiles: clinical presentation, and treatment response in cancer. Full text in Research Archive.
• Kaveh, Fatemeh; Baumbusch, Lars Oliver; Nebdal, Daniel J.H.; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian; Edvardsen, Hege; Kristensen, Vessela N. & Solvang, Hiroko Kato (2018). Correction: A systematic comparison of copy number alterations in four types of female cancer. BMC Cancer.  ISSN 1471-2407.  18(80) . doi: 10.1186/s12885-017-3766-7
• Vaske, Charlie; Bahrami, Nazli; Parulkar, R.; Newton, Y.; Sauer, Torill; Loeng, Marie; Gravdehaug, Berit; Bemanian, Vahid; Luders, Torben; Kristensen, Vessela N. & Geisler, Jürgen (2018). Time-course DNA and RNA profiling of tumors from intra-patient cross-over trial of sequential use of aromatase inhibitors.
• Bemanian, Vahid; Sauer, Torill; Touma, Joel Joul; Vetvik, Katja K; Noone, John Christopher; Kristensen, Vessela N.; Bukholm, Ida Rashida Khan & Geisler, Jürgen (2017). The EP300.G211S mutation is highly associated with low overall mutational burden in triple-negative breast cancer patients..
• Kristensen, Vessela N. (2017). The Antigenicity of the Tumor Cell — Context Matters. New England Journal of Medicine.  ISSN 0028-4793.  376, s 491- 493 . doi: 10.1056/NEJMcibr1613793
• Bemanian, Vahid; Sauer, Torill; Touma, Joel; Vetvik, Katja K; Chen, Ying; Kristensen, Vessela N.; Bukholm, Ida Rashida Khan & Geisler, Jürgen (2016). Next generation sequencing (NGS) reveals high mutation rates in established and potentially novel cancer genes in triple-negative breast cancer. Cancer Research.  ISSN 0008-5472.  76 . doi: 10.1158/1538-7445.AM2016-LB-246
• Bemanian, Vahid; Sauer, Torill; Touma, Joel; Vetvik, Katja K; Kristensen, Vessela N.; Bukholm, Ida Rashida Khan & Geisler, Jürgen (2016). Next generation sequencing (NGS) reveals high mutation rates in all established breast cancer subtypes with type-specific patterns.

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