Vessela N. Kristensen

• Akman, Tuğba; Arendt, Lisa M.; Geisler, Jürgen; Kristensen, Vessela N.; Frigessi, Arnoldo & Luque, Alvaro Kohn (2024). Modeling of Mouse Experiments Suggests that Optimal Anti-Hormonal Treatment for Breast Cancer is Diet-Dependent. Bulletin of Mathematical Biology. ISSN 0092-8240. 86(4). doi: 10.1007/s11538-023-01253-1.
• Morra, Anna; Schreurs, Maartje A. C.; Andrulis, Irene L.; Anton-Culver, Hoda; Augustinsson, Annelie & Beckmann, Matthias W. [Show all 125 contributors for this article] (2023). Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival. Cancer Medicine. ISSN 2045-7634. 12(15), p. 16142–16162. doi: 10.1002/cam4.6272. Full text in Research Archive
• Zanti, Maria; O'Mahony, Denise G.; Parsons, Michael T.; Li, Hongyan; Dennis, Joe & Aittomäkkiki, Kristiina [Show all 124 contributors for this article] (2023). A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2. Human Mutation. ISSN 1059-7794. 2023. doi: 10.1155/2023/9961341. Full text in Research Archive
• Mo, Torgeir; Brandal, Siri Helene Bertelsen; Geier, Oliver; Engebråten, Olav; Nilsen, Line & Kristensen, Vessela N. [Show all 10 contributors for this article] (2023). MRI Assessment of Changes in Tumor Vascularization during Neoadjuvant Anti-Angiogenic Treatment in Locally Advanced Breast Cancer Patients. Cancers. ISSN 2072-6694. 15(18). doi: 10.3390/cancers15184662. Full text in Research Archive
• Levi, Hagai; Carmi, Shai; Rosset, Saharon; Yerushalmi, Rinat; Zick, Aviad & Yablonski-Peretz, Tamar [Show all 155 contributors for this article] (2023). Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel. Journal of Medical Genetics. ISSN 0022-2593. 60(12), p. 1186–1197. doi: 10.1136/jmg-2023-109185. Full text in Research Archive
• Figlioli, Gisella; Billaud, Amandine; Wang, Qin; Bolla, Manjeet K.; Dennis, Joe & Lush, Michael [Show all 96 contributors for this article] (2023). Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases. Cancers. ISSN 2072-6694. 15(13). doi: 10.3390/cancers15133313. Full text in Research Archive
• Figlioli, Gisella; Billaud, Amandine; Ahearn, Thomas U.; Antonenkova, Natalia N.; Becher, Heiko & Beckmann, Matthias W. [Show all 114 contributors for this article] (2023). FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European Journal of Human Genetics. ISSN 1018-4813. 31(5), p. 578–587. doi: 10.1038/s41431-022-01257-w. Full text in Research Archive Show summary

  Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs

• Muranen, Taru A.; Morra, Anna; Khan, Sofia; Barnes, Daniel R.; Bolla, Manjeet K. & Dennis, Joe [Show all 69 contributors for this article] (2023). PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants. NPJ breast cancer. ISSN 2374-4677. 9:37(1), p. 1–15. doi: 10.1038/s41523-023-00546-x. Full text in Research Archive
• Chung, Felicia Fei-Lei; Maldonado, Sandra González; Nemc, Amelie; Bouaoun, Liacine; Cahais, Vincent & Cuenin, Cyrille [Show all 22 contributors for this article] (2023). Buffy coat signatures of breast cancer risk in a prospective cohort study. Clinical Epigenetics. ISSN 1868-7075. 15:102, p. 1–10. doi: 10.1186/s13148-023-01509-6. Full text in Research Archive
• Morra, Anna; Mavaddat, Nasim; Muranen, Taru A.; Ahearn, Thomas U.; Allen, Jamie & Andrulis, Irene L. [Show all 84 contributors for this article] (2023). The impact of coding germline variants on contralateral breast cancer risk and survival. American Journal of Human Genetics. ISSN 0002-9297. 110(3), p. 475–486. doi: 10.1016/j.ajhg.2023.02.003. Full text in Research Archive
• Daniel, Petr; Balušíková, Kamila; Václavíková, Radka; Šeborová, Karolína; Ransdorfová, Šárka & Valeriánová, Marie [Show all 14 contributors for this article] (2023). ABCB1 Amplicon Contains Cyclic AMP Response Element-Driven TRIP6 Gene in Taxane-Resistant MCF-7 Breast Cancer Sublines. Genes. ISSN 2073-4425. 14:296(2), p. 1–23. doi: 10.3390/genes14020296. Full text in Research Archive
• Svartdal, Lisa Gregusson; Haugen, Mads; Hongisto, Vesa; Aure, Miriam Ragle; Leivonen, Suvi-Katri & Kristensen, Vessela N. [Show all 10 contributors for this article] (2023). High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. PLOS ONE. ISSN 1932-6203. 18(1). doi: 10.1371/journal.pone.0280507. Full text in Research Archive
• Mueller, Stefanie H.; Lai, Alvina G.; Valkovskaya, Maria; Michailidou, Kyriaki; Bolla, Manjeet K. & Wang, Qin [Show all 207 contributors for this article] (2023). Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry. Genome Medicine. ISSN 1756-994X. 15(7). doi: 10.1186/s13073-022-01152-5. Full text in Research Archive
• Levy-Jurgenson, Alona; Tekpli, Xavier Kokou Mawu Yram; Kristensen, Vessela N. & Yakhini, Zohar (2023). Analysis of Spatial Molecular Data. Methods in molecular biology. ISSN 1064-3745. 2614, p. 349–356. doi: 10.1007/978-1-0716-2914-7_20.
• Grootes, Isabelle; Keeman, Renske; Blows, Fiona M.; Milne, Roger L.; Giles, Graham G. & Swerdlow, Anthony J. [Show all 55 contributors for this article] (2022). Incorporating progesterone receptor expression into the PREDICT breast prognostic model. European Journal of Cancer. ISSN 0959-8049. 173, p. 178–193. doi: 10.1016/j.ejca.2022.06.011. Full text in Research Archive
• Vitelli, Valeria; Fleischer, Thomas; Ankill, Jørgen; Arjas, Elja; Frigessi, Arnoldo & Kristensen, Vessela N. [Show all 7 contributors for this article] (2022). Transcriptomic pan-cancer analysis using rank-based Bayesian inference. Molecular Oncology. ISSN 1574-7891. 00(0), p. 1–16. doi: 10.1002/1878-0261.13354. Full text in Research Archive
• Seborova, Karolina; Hlavac, Viktor; Holy, Petr; Bjørklund, Sunniva; Fleischer, Thomas & Rob, Lukas [Show all 16 contributors for this article] (2022). Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy. Frontiers in Oncology. ISSN 2234-943X. 12:1016958, p. 1–16. doi: 10.3389/fonc.2022.1016958. Full text in Research Archive
• Dixon-Suen, Suzanne C.; Lewis, Sarah; Martin, Richard M.; English, Dallas R.; Boyle, Terry & Giles, Graham G. [Show all 174 contributors for this article] (2022). Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study. British Journal of Sports Medicine. ISSN 0306-3674. 56(20), p. 1157–1170. doi: 10.1136/bjsports-2021-105132. Show summary

  Objectives Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. Methods We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. Results Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). Conclusion Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

• Castro Mondragon, Jaime Abraham; Aure, Miriam Ragle; Lingjærde, Ole Christian; Langerød, Anita; Martens, John WM & Børresen-Dale, Anne-Lise [Show all 8 contributors for this article] (2022). Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(21), p. 12131–12148. doi: 10.1093/nar/gkac1143. Full text in Research Archive
• Ankill, Jørgen; Aure, Miriam Ragle; Bjørklund, Sunniva; Langberg, Geir Severin Rakh Elvatun; Kristensen, Vessela N. & Vitelli, Valeria [Show all 8 contributors for this article] (2022). Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer. NAR Cancer. ISSN 2632-8674. 4(1), p. 1–16. doi: 10.1093/narcan/zcac008. Full text in Research Archive Show summary

  Aberrant DNA methylation is an early event in breast carcinogenesis and plays a critical role in regulating gene expression. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL) analysis through the integration of DNA methylation and gene expression to identify disease-driving pathways under epigenetic control. By grouping the emQTLs using biclustering we identify associations representing important biological processes associated with breast cancer pathogenesis including regulation of proliferation and tumor-infiltrating fibroblasts. We report genome-wide loss of enhancer methylation at binding sites of proliferation-driving transcription factors including CEBP-β, FOSL1, and FOSL2 with concomitant high expression of proliferation-related genes in aggressive breast tumors as we confirm with scRNA-seq. The identified emQTL-CpGs and genes were found connected through chromatin loops, indicating that proliferation in breast tumors is under epigenetic regulation by DNA methylation. Interestingly, the associations between enhancer methylation and proliferation-related gene expression were also observed within known subtypes of breast cancer, suggesting a common role of epigenetic regulation of proliferation. Taken together, we show that proliferation in breast cancer is linked to loss of methylation at specific enhancers and transcription factor binding and gene activation through chromatin looping.

• Lirussi, Lisa; Ayyildiz, Dilara; Liu, Yan; Montaldo, Nicola Pietro; Carracedo Huroz, Sergio & Aure, Miriam Ragle [Show all 16 contributors for this article] (2022). A regulatory network comprising let-7 miRNA and SMUG1 is associated with good prognosis in ER+ breast tumours. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(18), p. 10449–10468. doi: 10.1093/nar/gkac807. Full text in Research Archive
• Tahiri, Andliena; Puco, Katarina; Naji, Faris; Kristensen, Vessela N.; Alfsen, G. Cecilie & Farkas, Lorant [Show all 10 contributors for this article] (2022). Kinase activity profiling in renal cell carcinoma, benign renal tissue and in response to four different tyrosine kinase inhibitors. OncoTarget. ISSN 1949-2553. 13(1), p. 970–981. doi: 10.18632/oncotarget.28257. Full text in Research Archive Show summary

  Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip® technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, ex vivo treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.

• Dorling, Leila; Carvalho, Sara; Allen, Jamie; Parsons, Michael T.; Fortuno, Cristina & Kristensen, Vessela N. [Show all 50 contributors for this article] (2022). Breast cancer risks associated with missense variants in breast cancer susceptibility genes. Genome Medicine. ISSN 1756-994X. 14(1), p. 1–17. doi: 10.1186/s13073-022-01052-8. Full text in Research Archive Show summary

  Background: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to ana‑ lyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to fve in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best ftting models were well calibrated in the validation set. Conclusions: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility

• Pedersen, Christine Aaserød; Cao, Maria Dung; Fleischer, Thomas; Rye, Morten Beck; Knappskog, Stian & Eikesdal, Hans Petter [Show all 12 contributors for this article] (2022). DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival. Breast Cancer Research. ISSN 1465-5411. 24:43(1), p. 1–14. doi: 10.1186/s13058-022-01537-9. Full text in Research Archive
• Bjørklund, Sunniva; Aure, Miriam Ragle; Häkkinen, Jari; Vallon-Christersson, Johan; Kumar, Surendra & Bull Evensen, Katrine [Show all 34 contributors for this article] (2022). Subtype and cell type specific expression of lncRNAs provide insight into breast cancer. Communications Biology. ISSN 2399-3642. 5(1), p. 1–14. doi: 10.1038/s42003-022-03559-7. Full text in Research Archive
• Chen, Hongjie; Fan, Shaoqi; Stone, Jennifer; Thompson, Deborah J.; Douglas, Julie & Kristensen, Vessela N. [Show all 56 contributors for this article] (2022). Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci. Breast Cancer Research. ISSN 1465-5411. 24:27(1), p. 1–15. doi: 10.1186/s13058-022-01524-0. Full text in Research Archive Show summary

  Background: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identifed genetic variants. Methods: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/ BCAC consortia. Results: We identifed 28 genome-wide signifcant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p<0.05. TWAS further identifed two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was signifcantly associated with MD phenotypes. Conclusions: Our fndings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer. Keywords: Mammographic density, Breast cancer, Genome-wide association study (GWAS), Transcriptome-wide association study (TWAS)

• Mo, Torgeir; Brandal, Siri Helene Bertelsen; Kohn Luque, Alvaro; Engebråten, Olav; Kristensen, Vessela N. & Fleischer, Thomas [Show all 8 contributors for this article] (2022). Quantification of Tumor Hypoxia through Unsupervised Modelling of Consumption and Supply Hypoxia MR Imaging in Breast Cancer. Cancers. ISSN 2072-6694. 14(5), p. 1–16. doi: 10.3390/cancers14051326. Full text in Research Archive Show summary

  Simple Summary Hypoxia in solid tumors is common in most solid cancers and is associated with treatment resistance to both chemo- and radiation-therapy. There is also reason to believe that hypoxia is an important determinant of metastic disease. Identifying hypoxia in solid tumors is important in treatment planning and decision making. In 2018 Hompland et al. proposed a method, based on quantifying consumption and supply of oxygen from diffusion weighted magnetic resonance imaging, to estimate the hypoxic fraction of a solid tumor. The method was based on training model parameters on a known hypoxia state in prostate cancer. In the present study we verified the validity of the consumption and supply concept in breast cancer. Furthermore, we developed and validated a new approach to the concept that does not require a ground truth to train the parameters. Abstract The purpose of the present study is to investigate if consumption and supply hypoxia (CSH) MR-imaging can depict breast cancer hypoxia, using the CSH-method initially developed for prostate cancer. Furthermore, to develop a generalized pan-cancer application of the CSH-method that doesn’t require a hypoxia reference standard for training the CSH-parameters. In a cohort of 69 breast cancer patients, we generated, based on the principles of intravoxel incoherent motion modelling, images reflecting cellular density (apparent diffusion coefficient; ADC) and vascular density (perfusion fraction; fp). Combinations of the information in these images were compared to a molecular hypoxia score made from gene expression data, aiming to identify a way to apply the CSH-methodology in breast cancer. Attempts to adapt previously proposed models for prostate cancer included direct transfers and model parameter rescaling. A novel approach, based on rescaling ADC and fp data to give more nuanced response in the relevant physiologic range, was also introduced. The new CSH-method was validated in a prostate cancer cohort with known hypoxia status. The proposed CSH-method gave estimates of hypoxia that was strongly correlated to the molecular hypoxia score in breast cancer, and hypoxia as measured in pathology slices stained with pimonidazole in prostate cancer. The generalized approach to CSH-imaging depicted hypoxia in both breast and prostate cancers and requires no model training. It is easy to implement using readily available technology and encourages further investigation of CSH-imaging in other cancer entities and in other settings, with the goal being to overcome hypoxia-induced resistance to treatment. Keywords: hypoxia; magnetic resonance imaging; diffusion weighted imaging; CSH

• Normann, Lisa Svartdal; Haugen, Mads Haugland; Aure, Miriam Ragle; Kristensen, Vessela N.; Mælandsmo, Gunhild Mari & Sahlberg, Kristine Kleivi (2022). miR-101-5p Acts as a Tumor Suppressor in HER2-Positive Breast Cancer Cells and Improves Targeted Therapy. Breast Cancer: Targets and Therapy. ISSN 1179-1314. 14, p. 25–39. doi: 10.2147/BCTT.S338404. Full text in Research Archive Show summary

  Purpose: Human epidermal growth factor receptor 2 positive (HER2+) breast cancers responding poorly to targeted therapy need improved treatment options. miR-101-5p has shown tumor-suppressive properties in multiple cancer forms, and we assessed the effect and mechanism of action of this miRNA in HER2+ breast cancer. Methods: Expression levels of miR-101-5p in two clinical datasets, TCGA and METABRIC, were compared between tumor and normal adjacent samples, and across molecular subtypes and HER2 status. The ability of miR-101-5p to sensitize for treatment with lapatinib, tucatinib and trastuzumab was explored in HER2+ breast cancer cells responding poorly to such targeted drugs. Proliferation and apoptosis assays and downstream protein analysis were performed. Results: Expression levels of miR-101-5p were significantly lower in tumor compared to normal adjacent tissue (p < 0.001), and particularly low in HER2+ tumors, both the HER2-enriched subtype (p ≤ 0.037) and clinical HER2-status (p < 0.001). In a HER2+ cell line (KPL4) responding poorly to targeted drugs, miR-101-5p overexpression inhibited proliferation (p < 0.001), and combinatorial treatment with lapatinib and trastuzumab significantly further decreased this inhibition (p = 0.004). Proteomic data and in silico analyses revealed PI3K/Akt- and HER2-pathways among the predicted regulated pathways. miR-101-5p alone (p = 0.018) and in combination with lapatinib and trastuzumab (p < 0.001) induced apoptosis, while the targeted drugs alone did not exert any significant effect neither on proliferation nor apoptosis. Conclusion: miR-101-5p acts as a tumor suppressor by inducing apoptosis in HER2+ breast cancer and sensitizes cells with initially poor response to lapatinib and trastuzumab.

• Mavaddat, Nasim; Dorling, Leila; Carvalho, Sara; Allen, Jamie; González-Neira, Anna & Keeman, Renske [Show all 94 contributors for this article] (2022). Pathology of tumors associated with pathogenic germline variants in 9 breast cancer susceptibility genes. JAMA Oncology. ISSN 2374-2437. 8(3). doi: 10.1001/jamaoncol.2021.6744. Show summary

  IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ ERBB2− high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ ERBB2+ and HR– ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. CONCLUSIONS AND RELEVANCE The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

• Dennis, Joe; Tyrer, Jonathan P.; Walker, Logan C.; Michailidou, Kyriaki; Dorling, Leila & Kristensen, Vessela N. [Show all 50 contributors for this article] (2022). Rare germline copy number variants (CNVs) and breast cancer risk. Communications Biology. ISSN 2399-3642. 5, p. 1–15. doi: 10.1038/s42003-021-02990-6. Full text in Research Archive Show summary

  Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

• Ahearn, Thomas U.; Zhang, Haoyu; Michailidou, Kyriaki; Milne, Roger L.; Bolla, Manjeet K. & Dennis, Joe [Show all 205 contributors for this article] (2022). Common variants in breast cancer risk loci predispose to distinct tumor subtypes. Breast Cancer Research. ISSN 1465-5411. 24(1), p. 1–13. doi: 10.1186/s13058-021-01484-x. Full text in Research Archive
• Lemma, Roza Berhanu; Fleischer, Thomas; Martinsen, Emily; Ledsaak, Marit; Kristensen, Vessela N. & Eskeland, Ragnhild [Show all 8 contributors for this article] (2022). Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers. Epigenetics & Chromatin. ISSN 1756-8935. 15. doi: 10.1186/s13072-022-00444-9. Full text in Research Archive Show summary

  Methylation of cytosines on DNA is a prominent modification associated with gene expression regulation. Aberrant DNA methylation patterns have recurrently been linked to dysregulation of the regulatory program in cancer cells. To shed light on the underlying molecular mechanism driving this process, we hypothesised that aberrant methylation patterns could be controlled by the binding of specific transcription factors (TFs) across cancer types. By combining DNA methylation arrays and gene expression data with TF binding sites (TFBSs), we explored the interplay between TF binding and DNA methylation in 19 cancer types. We performed emQTL (expression–methylation quantitative trait loci) analyses independently in each cancer type and identified 13 TFs whose expression levels are correlated with local DNA methylation patterns around their binding sites in at least 2 cancer types. The 13 TFs are mainly associated with local demethylation and are enriched for pioneer function, suggesting a specific role for these TFs in modulating chromatin structure and transcription in cancer patients. Furthermore, we confirmed that de novo methylation is precluded across cancers at CpGs lying in genomic regions enriched for TF binding signatures associated with SP1, CTCF, NRF1, GABPA, KLF9, and/or YY1. The modulation of DNA methylation associated with TF binding was observed at cis-regulatory regions controlling immune- and cancer-associated pathways, corroborating that the emQTL signals were derived from both cancer and tumor-infiltrating cells. As a case example, we experimentally confirmed that FOXA1 knock-down is associated with higher methylation in regions bound by FOXA1 in breast cancer MCF-7 cells. Finally, we reported physical interactions between FOXA1 with TET1 and TET2 both in an in vitro setup and in vivo at physiological levels in MCF-7 cells, adding further support for FOXA1 attracting TET1 and TET2 to induce local demethylation in cancer cells.

• Dorling, Leila; Carvalho, Sara; Allen, Jamie; González-Neira, Anna; Luccarini, Craig & Wahlström, Cecilia [Show all 176 contributors for this article] (2021). Breast cancer risk genes - Association analysis in more than 113,000 women. New England Journal of Medicine. ISSN 0028-4793. 384(5), p. 428–439. doi: 10.1056/NEJMoa1913948.
• Park, Hanla A.; Neumeyer, Sonja; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin & Kristensen, Vessela N. [Show all 50 contributors for this article] (2021). Mendelian randomisation study of smoking exposure in relation to breast cancer risk. British Journal of Cancer. ISSN 0007-0920. 125(8), p. 1135–1145. doi: 10.1038/s41416-021-01432-8. Full text in Research Archive
• Johnson, Nichola; Maguire, Sarah; Morra, Anna; Kapoor, Pooja Middha; Tomczyk, Katarzyna & Kristensen, Vessela N. [Show all 50 contributors for this article] (2021). CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers. British Journal of Cancer. ISSN 0007-0920. 124, p. 842–854. doi: 10.1038/s41416-020-01185-w. Full text in Research Archive
• Rye, Inga Hansine; Huse, Kanutte; Josefsson, Sarah Elisabet; Kildal, Wanja; Danielsen, Håvard Emil Greger & Schlichting, Ellen [Show all 28 contributors for this article] (2021). Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression. Molecular Oncology. ISSN 1574-7891. 16(1), p. 88–103. doi: 10.1002/1878-0261.13047. Full text in Research Archive
• Morra, Anna; Jung, Audrey Y.; Behrens, Sabine; Keeman, Renske; Ahearn, Thomas U. & Anton-Culver, Hoda [Show all 134 contributors for this article] (2021). Breast cancer risk factors and survival by tumor subtype: Pooled analyses from the breast cancer association consortium. Cancer Epidemiology, Biomarkers and Prevention. ISSN 1055-9965. 30(4), p. 623–642. doi: 10.1158/1055-9965.EPI-20-0924.
• Baxter, Joseph S.; Johnson, Nichola; Tomczyk, Katarzyna; Gillespie, Andrea; Maguire, Sarah & Brough, Rachel [Show all 183 contributors for this article] (2021). Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. American Journal of Human Genetics. ISSN 0002-9297. 108(7), p. 1190–1203. doi: 10.1016/j.ajhg.2021.05.013. Full text in Research Archive
• Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Keeman, Renske; Canisius, Sander & Ahearn, Thomas U. [Show all 50 contributors for this article] (2021). Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. Breast Cancer Research. ISSN 1465-5411. 23:86(1), p. 1–18. doi: 10.1186/s13058-021-01450-7. Full text in Research Archive
• Escala-Garcia, Maria; Canisius, Sander; Keeman, Renske; Beesley, Jonathan; Anton-Culver, Hoda & Arndt, Volker [Show all 105 contributors for this article] (2021). Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis. Scientific Reports. ISSN 2045-2322. 11:19787, p. 1–11. doi: 10.1038/s41598-021-99409-3. Full text in Research Archive Show summary

  Breast cancer metastasis accounts for most of the deaths from breast cancer. Identifcation of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identifed two germline variants on chromosome 1, rs138569520 and rs146023652, signifcantly associated with breast cancer-specifc survival (P= 3.19 × ­10−8 and 4.42 × ­10−8). In silico analysis suggested a potential regulatory efect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confrm the identifed associations.

• Fores-Martos, Jaume; Cervera-Vidal, Raimundo; Sierra-Roca, Julia; Lozano-Asencio, Carlos; Fedele, Vita & Cornelissen, Sten [Show all 19 contributors for this article] (2021). Circadian PERformance in breast cancer: a germline and somatic genetic study of PER3 ^VNTR polymorphisms and gene co-expression. NPJ breast cancer. ISSN 2374-4677. 7(1). doi: 10.1038/s41523-021-00329-2.
• Park, JooYong; Choi, Ji-Yeob; Choi, Jaesung; Chung, Seokang; Song, Nan & Park, Sue K [Show all 50 contributors for this article] (2021). Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies? Cancers. ISSN 2072-6694. 13:2370(10), p. 1–21. doi: 10.3390/cancers13102370. Full text in Research Archive
• Galili, Ben; Tekpli, Xavier; Kristensen, Vessela N. & Yakhini, Zohar (2021). Efficient gene expression signature for a breast cancer immuno-subtype. PLOS ONE. ISSN 1932-6203. 16(1). doi: 10.1371/journal.pone.0245215.
• Bahrami, Nazli; Jabeen, Shakila; Tahiri, Andliena; Sauer, Torill; Ødegård, Hilde Presterud & Geisler, Stephanie Beate [Show all 11 contributors for this article] (2021). Lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients: the potential role of the adipokine leptin. Breast Cancer Research and Treatment. ISSN 0167-6806. 190, p. 435–449. doi: 10.1007/s10549-021-06399-x. Full text in Research Archive
• Ben-Elazar, Shay; Aure, Miriam Ragle; Jonsdottir, Kristin; Leivonen, Suvi-Katri; Kristensen, Vessela N. & Janssen, Emiel [Show all 9 contributors for this article] (2021). miRNA normalization enables joint analysis of several datasets to increase sensitivity and to reveal novel miRNAs differentially expressed in breast cancer. PLoS Computational Biology. ISSN 1553-734X. 17(2). doi: 10.1371/JOURNAL.PCBI.1008608. Full text in Research Archive
• Aure, Miriam Ragle; Fleischer, Thomas; Bjørklund, Sunniva; Ankill, Jørgen; Castro Mondragón, Jaime Abraham & Børresen-Dale, Anne-Lise [Show all 11 contributors for this article] (2021). Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer. Genome Medicine. ISSN 1756-994X. 13:72, p. 1–21. doi: 10.1186/s13073-021-00880-4. Full text in Research Archive
• Svartdal Normann, Lisa Gregusson; Aure, Miriam Ragle; Leivonen, Suvi-Katri; Haugen, Mads Haugland; Hongisto, Vesa & Kristensen, Vessela N. [Show all 8 contributors for this article] (2021). MicroRNA in combination with HER2-targeting drugs reduces breast cancer cell viability in vitro. Scientific Reports. ISSN 2045-2322. 11:10893, p. 1–11. doi: 10.1038/s41598-021-90385-2. Full text in Research Archive
• Graim, Kiley; Gorenshteyn, Dmitriy; Robinson, David G; Carriero, Nicholas J; Cahill, James A. & Chakrabarti, Rumela [Show all 14 contributors for this article] (2021). Modeling molecular development of breast cancer in canine mammary tumors. Genome Research. ISSN 1088-9051. 31(3), p. 337–347. doi: 10.1101/GR.256388.119.
• Zhang, Haoyu; Ahearn, Thomas U.; Lecarpentier, Julie; Barnes, Daniel; Beesley, Jonathan & Qi, Guanghao [Show all 272 contributors for this article] (2020). Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nature Genetics. ISSN 1061-4036. 52(6), p. 572–581. doi: 10.1038/s41588-020-0609-2.
• Feng, Helian; Gusev, Alexander; Pasaniuc, Bogdan; Wu, Lang; Long, Jirong & Kristensen, Vessela N. [Show all 50 contributors for this article] (2020). Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status. Genetic Epidemiology. ISSN 0741-0395. 44(5), p. 442–468. doi: 10.1002/gepi.22288. Full text in Research Archive
• Fachal, Laura; Aschard, Hugues; Beesley, Jonathan; Barnes, Daniel R.; Allen, Jamie & Kristensen, Vessela N. [Show all 50 contributors for this article] (2020). Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature Genetics. ISSN 1061-4036. 52(1), p. 56–73. doi: 10.1038/s41588-019-0537-1. Full text in Research Archive
• Escala-Garcia, Maria; Abraham, Jean; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker & Børresen-Dale, Anne-Lise [Show all 51 contributors for this article] (2020). A network analysis to identify mediators of germline-driven differences in breast cancer prognosis. Nature Communications. ISSN 2041-1723. 11:312, p. 1–14. doi: 10.1038/s41467-019-14100-6. Full text in Research Archive
• Liu, Jingjing; van der Smissen, Wendy J. C. Prager; Collee, Margriet J.; Bolla, Manjeet K.; Wang, Qin & Kristensen, Vessela N. [Show all 82 contributors for this article] (2020). Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk. Scientific Reports. ISSN 2045-2322. 10:9688(1), p. 1–14. doi: 10.1038/s41598-020-65665-y. Full text in Research Archive Show summary

  In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR=1.035, 95% CI=0.859–1.246, P=0.718 and OR=0.798, 95% CI=0.482–1.322, P=0.381 respectively), nor in specifc high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

• Bergholtz, Helga; Kumar, Surendra; Wärnberg, Fredrik; Luders, Torben; Kristensen, Vessela N. & Sørlie, Therese (2020). Comparable cancer-relevant mutation profiles in synchronous ductal carcinoma in situ and invasive breast cancer. Cancer Reports. ISSN 2573-8348. 3:e1248(3), p. 1–7. doi: 10.1002/cnr2.1248. Full text in Research Archive
• Kramer, Iris; Hooning, Maartje J.; Mavaddat, Nasim; Hauptmann, Michael; Keeman, Renske & Steyerberg, Ewout W. [Show all 54 contributors for this article] (2020). Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk. American Journal of Human Genetics. ISSN 0002-9297. 107(5), p. 837–848. doi: 10.1016/j.ajhg.2020.09.001. Show summary

  Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18–1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02–1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547–0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

• Levy-Jurgenson, Alona; Tekpli, Xavier; Kristensen, Vessela N. & Yakhini, Zohar (2020). Spatial transcriptomics inferred from pathology whole-slide images links tumor heterogeneity to survival in breast and lung cancer. Scientific Reports. ISSN 2045-2322. 10:18802, p. 1–11. doi: 10.1038/s41598-020-75708-z. Full text in Research Archive
• Tinholt, Mari; Stavik, Benedicte; Tekpli, Xavier; Garred, Øystein; Borgen, Elin & Kristensen, Vessela N. [Show all 9 contributors for this article] (2020). Coagulation factor V is a marker of tumor-infiltrating immune cells in breast cancer. Oncoimmunology. ISSN 2162-4011. 9:e1824644(1), p. 1–12. doi: 10.1080/2162402X.2020.1824644. Full text in Research Archive
• Tahiri, Andliena; Tekpli, Xavier; Somisetty, Venkata Satheesh; DeWijn, Rik; Luders, Torben & Bukholm, Ida Rashida Khan [Show all 9 contributors for this article] (2020). Loss of progesterone receptor is associated with distinct tyrosine kinase profiles in breast cancer. Breast Cancer Research and Treatment. ISSN 0167-6806. 183, p. 585–598. doi: 10.1007/s10549-020-05763-7. Full text in Research Archive Show summary

  Abstract Purpose The aim of this study was to assess protein tyrosine kinase profles in primary breast cancer samples in correlation with the distinct hormone and growth receptor profles ER, PR, and HER2. Experimental design Pamchip® microarrays were used to measure the phosphorylation of 144 tyrosine kinase substrates in 29 ER+breast cancer samples and cell lines MCF7, BT474 and ZR75-1. mRNA expression data from the METABRIC cohort and publicly available PR chip-sequencing data were used for validation purposes, together with RT-PCR. Results In ER+ breast tumors and cell lines, we observed that the loss of PR expression correlated to higher kinase activity in samples and cell lines that were HER2−. A number of kinases, representing mostly proteins within the PI3K/AKT pathway, were identifed as responsible for the diferential phosphorylation between PR− and PR+ in ER+/HER2− tumors. We used the METABRIC cohort to analyze mRNA expression from 977 ER+/HER2− breast cancers. Twenty four kinaseencoding genes were identifed as diferentially expressed between PR+ and PR−, dividing ER+/HER2− samples in two distinct clusters with signifcant diferences in survival (p<0.05). Four kinase genes, LCK, FRK, FGFR4, and MST1R, were identifed as potential direct targets of PR. Conclusions Our results suggest that the PR status has a profound efect on tyrosine kinases, especially for FGFR4 and LCK genes, in ER+/HER2− breast cancer patients. The infuence of these genes on the PI3K/AKT signaling pathway may potentially lead to novel drug targets for ER+/PR− breast cancer patients

• Pladsen, Arne Valebjørg; Nilsen, Gro; Rueda, Oscar M.; Aure, Miriam Ragle; Borgan, Ørnulf & Liestøl, Knut [Show all 18 contributors for this article] (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. Full text in Research Archive
• Egeland, Nina Gran; Jonsdottir, Kristin; Aure, Miriam Ragle; Sahlberg, Kristine Kleivi; Kristensen, Vessela N. & Cronin-Fenton, Deirdre [Show all 10 contributors for this article] (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. Full text in Research Archive
• Gythfeldt, Hedda von der Lippe; Lien, Tonje Gulbrandsen; Tekpli, Xavier; Silwal-Pandit, Laxmi; Borgen, Elin & Garred, Øystein [Show all 15 contributors for this article] (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), p. 2515–2525. doi: 10.1002/ijc.33108. Full text in Research Archive
• Ree, Anne Hansen; Nygaard, Vigdis; Pedersen, Kjetil Boye; Heinrich, Daniel; Dueland, Svein & Bergheim, Inger Riise [Show all 25 contributors for this article] (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. p. 1–10. doi: 10.1080/0284186X.2020.1742377. Full text in Research Archive
• 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), p. 994–999. doi: 10.1093/bioinformatics/btz709. Full text in Research Archive Show summary

  Abstract Motivation: Breast cancer consists of multiple distinct tumor subtypes, and results from epigenetic and genetic aberrations that give rise to distinct transcriptional profiles. Despite previous efforts to understand transcriptional deregulation through transcription factor networks, the transcriptional mechanisms leading to subtypes of the disease remain poorly understood. Results: We used a sophisticated computational search of thousands of expression datasets to define extended signatures of distinct breast cancer subtypes. Using ENCODE ChIP-seq data of surrogate cell lines and motif analysis we observed that these subtypes are determined by a distinct repertoire of lineage-specific transcription factors. Furthermore, specific pattern and abundance of copy number and DNA methylation changes at these TFs and targets, compared to other genes and to normal cells were observed. Overall, distinct transcriptional profiles are linked to genetic and epigenetic alterations at lineage-specific transcriptional regulators in breast cancer subtypes. Availability and implementation: The analysis code and data are deposited at https://bitbucket.org/qzhu/breast.cancer.tf/.

• Shu, Xiang; Wu, Lang; Khankari, Nikhil K.; Shu, Xiao-Ou; Wang, Thomas J & Michailidou, Kyriaki [Show all 51 contributors for this article] (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), p. 795––806. doi: 10.1093/ije/dyy201.
• Tekpli, Xavier; Lien, Tonje Gulbrandsen; Røssevold, Andreas Hagen; Nebdal, Daniel J.H.; Borgen, Elin & Ohnstad, Hege Oma [Show all 19 contributors for this article] (2019). An independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment. Nature Communications. ISSN 2041-1723. 10:5499, p. 1–14. doi: 10.1038/s41467-019-13329-5. Full text in Research Archive
• Nome, Marianne Eikhom; Euceda, Leslie R.; Jabeen, Shakila; Debik, Julia; Bathen, Tone Frost & Giskeødegård, Guro F. [Show all 17 contributors for this article] (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), p. 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 [Show all 24 contributors for this article] (2019). miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer. Cell reports. ISSN 2211-1247. 29(13), p. 4389–4406.e10. doi: 10.1016/j.celrep.2019.11.085.
• 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, p. 179–190. doi: 10.1007/978-3-030-18174-1_13.
• Dörk, Thilo; Peterlongo, Paolo; Mannermaa, Arto; Bolla, Manjeet K.; Wang, Qin & Dennis, Joe [Show all 170 contributors for this article] (2019). Two truncating variants in FANCC and breast cancer risk. Scientific Reports. ISSN 2045-2322. 9, p. 1–14. doi: 10.1038/s41598-019-48804-y. Full text in Research Archive
• Lindholm, Evita Maria; Aure, Miriam Ragle; Haugen, Mads Haugland; Sahlberg, Kristine Kleivi; Kristensen, Vessela N. & Nebdal, Daniel J.H. [Show all 9 contributors for this article] (2019). miRNA expression changes during the course of neoadjuvant bevacizumab and chemotherapy treatment in breast cancer. Molecular Oncology. ISSN 1574-7891. 13(10), p. 2278–2296. doi: 10.1002/1878-0261.12561. Full text in Research Archive
• Václavíková, Radka; Klajic, Jovana; Brynychová, Veronika; Elsnerova, Katerina; Grenaker, Grethe Irene & Tost, Jörg [Show all 12 contributors for this article] (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), p. 763–774. doi: 10.3892/or.2019.7186.
• Bahrami, Nazli; Sauer, Torill; Engebretsen, Siri Strøm; Aljabri, Mohammad Belal; Bemanian, Vahid & Lindstrøm, Jonas Christoffer [Show all 17 contributors for this article] (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), p. 3675–3682. doi: 10.2217/fon-2019-0258. Full text in Research Archive
• Escala-Garcia, Maria; Guo, Qi; Dörk, Thilo; Canisius, Sander; Keeman, Renske & Dennis, Joe [Show all 236 contributors for this article] (2019). Genome-wide association study of germline variants and breast cancer-specific mortality. British Journal of Cancer. ISSN 0007-0920. 120(6), p. 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 [Show all 210 contributors for this article] (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.

• Lai, Xiaoran; Geier, Oliver; Fleischer, Thomas; Garred, Øystein; Borgen, Elin & Funke, Simon Wolfgang [Show all 14 contributors for this article] (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), p. 4293–4304. doi: 10.1158/0008-5472.CAN-18-1804. Full text in Research Archive
• Johansson, Henrik J.; Socciarelli, Fabio; Vacanti, Nathaniel M.; Haugen, Mads Haugland; Zhu, Yafeng & Siavelis, Ioannis [Show all 36 contributors for this article] (2019). Breast cancer quantitative proteome and proteogenomic landscape. Nature Communications. ISSN 2041-1723. 10:1600, p. 1–14. doi: 10.1038/s41467-019-09018-y. Full text in Research Archive
• Brinkman, Arie B.; Nik-Zainal, Serena; Simmer, Femke; Rodríguez-González, F. Germán; Smid, Marcel & Alexandrov, Ludmil B. [Show all 29 contributors for this article] (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
• Lee, Young-suk; Krishnan, Arjun; Oughtred, Rose; Rust, Jennifer; Chang, Christie S. & Ryu, Joseph [Show all 10 contributors for this article] (2019). A Computational Framework for Genome-wide Characterization of the Human Disease Landscape. Cell Systems. ISSN 2405-4712. 8(2), p. 152–162.e6. doi: 10.1016/j.cels.2018.12.010.
• Jiang, Xia; Finucane, Hilary K.; Schumacher, Fredrick R.; Schmit, Stephanie L.; Tyrer, Jonathan P. & Han, Younghun [Show all 333 contributors for this article] (2019). Shared heritability and functional enrichment across six solid cancers. Nature Communications. ISSN 2041-1723. 10:431, p. 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.

• Nguyen, Chinh BKrong; Kumar, Surendra; Zucknick, Manuela; Kristensen, Vessela N.; Gjerstad, Johannes & Nilsen, Hilde Loge [Show all 7 contributors for this article] (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, p. 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.

• Tahiri, Andliena; Aure, Miriam Ragle & Kristensen, Vessela N. (2018). MicroRNA Networks in Breast Cancer Cells. Methods in molecular biology. ISSN 1064-3745. 1711, p. 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.

• Mavaddat, Nasim; Michailidou, Kyriaki; Dennis, Joe; Lush, Michael; Fachal, Laura & Lee, Andrew [Show all 56 contributors for this article] (2018). Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. American Journal of Human Genetics. ISSN 0002-9297. 104(1), p. 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 [Show all 19 contributors for this article] (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
• Jabeen, Shakila; Espinoza, Jaime; Torland, Lilly Anne; Zucknick, Manuela; Kumar, Surendra & Haakensen, Vilde Drageset [Show all 15 contributors for this article] (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
• Tinholt, Mari; Garred, Øystein; Borgen, Elin; Beraki, Else; Schlichting, Ellen & Kristensen, Vessela N. [Show all 8 contributors for this article] (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), p. 1347–1356. doi: 10.1111/jth.14151.
• Jabeen, Shakila; Zucknick, Manuela; Nome, Marianne Eikhom; dannenfelser, ruth; Fleischer, Thomas & Kumar, Surendra [Show all 15 contributors for this article] (2018). Serum cytokine levels in breast cancer patients during neoadjuvant treatment with bevacizumab. Oncoimmunology. ISSN 2162-4011. 7(11), p. e1457598-1–e1457598-15. doi: 10.1080/2162402X.2018.1457598.
• Prasmickaite, Lina; Tenstad, Ellen; Pettersen, Solveig; Jabeen, Shakila; Egeland, Eivind Valen & Nord, Silje [Show all 12 contributors for this article] (2018). Basal-like breast cancer engages tumor-supportive macrophages via secreted factors induced by extracellular S100A4. Molecular Oncology. ISSN 1574-7891. 12(9), p. 1540–1558. doi: 10.1002/1878-0261.12319. Full text in Research Archive
• O'Mara, Tracy A.; Glubb, Dylan M.; Amant, Frédéric; Annibali, Daniela; Ashton, Katie & Attia, John [Show all 125 contributors for this article] (2018). Identification of nine new susceptibility loci for endometrial cancer. Nature Communications. ISSN 2041-1723. 9:3166, p. 1–12. doi: 10.1038/s41467-018-05427-7. Full text in Research Archive
• Bemanian, Vahid; Noone, John Christopher; Sauer, Torill; Touma, Joel Joul; Vetvik, Katja K & Söderberg-Naucler, Cecilia [Show all 10 contributors for this article] (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, p. 339–351. doi: 10.1007/s10549-018-4927-3.
• Wu, Lang; Shi, Wei; Long, Jirong; Guo, Xingyi; Michailidou, Kyriaki & Beesley, Jonathan [Show all 210 contributors for this article] (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), p. 968–978. doi: 10.1038/s41588-018-0132-x.

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• Frigessi Di Rattalma, Arnoldo; Köhn-Luque, Alvaro; Kristensen, Vessela N.; Gørbitz, Carl Henrik & Engebråten, Olav (2020). Kan statistikk og matematikk redde like mange liv som nye medisiner? Aftenposten (morgenutg. : trykt utg.). ISSN 0804-3116.
• Jiang, Xia; Finucane, Hilary K.; Schumacher, Fredrick; Schmit, Stephanie L.; Tyrer, Jonathan P. & Han, Younghun [Show all 333 contributors for this article] (2019). Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature Communications, (2019), 10, 1, (431), 10.1038/s41467-018-08054-4). Nature Communications. ISSN 2041-1723. 10(1). doi: 10.1038/s41467-019-12095-8.
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason J. & Russnes, Hege Elisabeth Giercksky [Show all 18 contributors for this article] (2019). Correction to: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors (Nature Communications, (2017), 8, 1, (1221), 10.1038/s41467-017-01355-0). Nature Communications. ISSN 2041-1723. 10(1). doi: 10.1038/s41467-019-08512-7.
• Tinholt, Mari; Stavik, Benedicte; Sletten, Marit; Garred, Øystein; Tekpli, Xavier & Kristensen, Vessela N. [Show all 9 contributors for this article] (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 [Show all 9 contributors for this article] (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; 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.
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason J. & Russnes, Hege Elisabeth Giercksky [Show all 18 contributors for this article] (2018). Author Correction: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors. Nature Communications. ISSN 2041-1723. 9(1). doi: 10.1038/s41467-018-07842-2.
• Vaske, Charlie; Bahrami, Nazli; Parulkar, R.; Newton, Y.; Sauer, Torill & Loeng, Marie [Show all 11 contributors for this article] (2018). Time-course DNA and RNA profiling of tumors from intra-patient cross-over trial of sequential use of aromatase inhibitors.
• Bahrami, Nazli; Sauer, Torill; Loeng, Marie; Gravdehaug, Berit; Engebretsen, Siri & Aljabri, Belal [Show all 11 contributors for this article] (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. Universitetet i Oslo. ISSN 978-82-8377-305-7. Full text in Research Archive

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