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Glodzik, Dominik,Morganella, Sandro,Davies, Helen,Simpson, Peter T,Li, Yilong,Zou, Xueqing,Diez-Perez, Javier,Staaf, Johan,Alexandrov, Ludmil B,Smid, Marcel,Brinkman, Arie B,Rye, Inga Hansine,Russnes, Nature Publishing Group, a division of Macmillan P 2017 Nature genetics Vol.49 No.11
This corrects the article DOI: 10.1038/ng.3771
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
Davies, Helen,Glodzik, Dominik,Morganella, Sandro,Yates, Lucy R,Staaf, Johan,Zou, Xueqing,Ramakrishna, Manasa,Martin, Sancha,Boyault, Sandrine,Sieuwerts, Anieta M,Simpson, Peter T,King, Tari A,Raine, Nature Publishing Group, a division of Macmillan P 2017 Nature medicine Vol.23 No.4
<P>Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (similar to 1-5%) who could have selective therapeutic sensitivity to PARP inhibition.</P>
Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
Davies, Helen,Morganella, Sandro,Purdie, Colin A.,Jang, Se Jin,Borgen, Elin,Russnes, Hege,Glodzik, Dominik,Zou, Xueqing,Viari, Alain,Richardson, Andrea L.,Børresen-Dale, Anne-Lise,Thompson, Alastair,E American Association for Cancer Research 2017 Cancer Research Vol.77 No.18
<P>The effectiveness of PD-1 blockade against DNA mismatch repair-deficient cancers makes it paramount to reliably identify the relatively rare cases beyond those with Lynch syndrome–associated colon cancers.</P><P>Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. <I>Cancer Res; 77(18); 4755–62. ©2017 AACR</I>.</P>