Publications
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Bruun, Jarle; Kryeziu, Kushtrim; Eide, Peter Andreas Wold; Moosavi, Seyed Hossein; Eilertsen, Ina Andrassy & Røsok, Bård Ingvald
[Show all 21 contributors for this article]
(2020).
Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity.
Clinical Cancer Research.
ISSN 1078-0432.
26(15),
p. 4107–4119.
doi:
10.1158/1078-0432.CCR-19-3637.
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Abstract
Purpose: Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer.
Experimental Design: We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients.
Results: Three drug–response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2–5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression.
Conclusions: Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression–based predictive signatures to guide experimental therapies.
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Langerud, Jonas; Jarhelle, Elisabeth; Van Ghelue, Marijke; Ariansen, Sarah Louise & Iversen, Nina
(2018).
Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance.
Human Genomics.
ISSN 1473-9542.
12(51).
doi:
10.1186/s40246-018-0183-1.
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Background: Deleterious variants in the tumour suppressor BRCA1 are known to cause hereditary breast and
ovarian cancer syndrome (HBOC). Missense variants in BRCA1 pose a challenge in clinical care, as their effect on
protein functionality often remains unknown. Many of the pathogenic missense variants found in BRCA1 are located
in the BRCA1 C-terminal (BRCT) domains, domains that are known to be vital for key functions such as homologous
recombination repair, protein-protein interactions and trans-activation (TA). We investigated the TA activity of 12
BRCA1 variants of unknown clinical significance (VUSs) located in the BRCT domains to aid in the classification of
these variants.
Results: Twelve BRCA1 VUSs were investigated using a modified version of the dual luciferase TA activity assay (TA
assay) that yielded increased sensitivity and sample throughput. Variants were classified according to American
College of Medical Genetics and Genomics (ACMG) criteria using TA assay results and available data. In combining
our TA-assay results and available data, in accordance with the ACMG guidelines for variant classification, we
proposed the following variant classifications: c.5100A>G, c.5326C>T, c.5348T>C and c.5477A>T as likely benign
(class 2) variants. c.5075A>C, c.5116G>A and c.5513T>G were likely pathogenic (class 4), whereas c.5096G>A likely
represents a likely pathogenic variant with moderate penetrance. Variants c.5123C>T, c.5125G>A, c.5131A>C and c.
5504G>A remained classified as VUSs (class 3).
Conclusions: The modified TA assay provides efficient risk assessment of rare missense variants found in the BRCA1
BRCT-domains. We also report that increased post-transfection incubation time yielded a significant increase in TA assay sensitivity.
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Published
Sep. 21, 2018 11:58 AM
- Last modified
Sep. 21, 2018 11:58 AM