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HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures

Davies, Helen R.; Glodzik, Dominik LU ; Morganella, Sandro; Yates, Lucy R.; Staaf, Johan LU ; Zou, Xueqing; Ramakrishna, Manasa; Martin, Sancha; Boyault, Sandrine and Sieuwerts, Anieta M., et al. (2017) In Nature Medicine 23(4). p.517-525
Abstract

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... (More)

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 (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.

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@article{4e4e1060-af63-4d40-ac78-1dc69f05ee99,
  abstract     = {<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 (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.</p>},
  author       = {Davies, Helen R. and Glodzik, Dominik and Morganella, Sandro and Yates, Lucy R. and Staaf, Johan and Zou, Xueqing and Ramakrishna, Manasa and Martin, Sancha and Boyault, Sandrine and Sieuwerts, Anieta M. and Simpson, Peter T and King, Tari A and Raine, Keiran and Eyfjord, Jorunn E. and Kong, Gu and Borg, Åke and Birney, Ewan and Stunnenberg, Hendrik G. and van de Vijver, Marc J and Børresen-Dale, Anne-Lise and Martens, John W. M. and Span, Paul N. and Lakhani, Sunil R. and Vincent-Salomon, Anne and Sotiriou, Christos and Tutt, Andrew and Thompson, Alastair M and Van Laere, Steven and Richardson, Andrea L. and Viari, Alain and Campbell, Peter J. and Stratton, Michael R. and Nik-Zainal, Serena},
  issn         = {1546-170X},
  language     = {eng},
  number       = {4},
  pages        = {517--525},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures},
  url          = {http://dx.doi.org/10.1038/nm.4292},
  volume       = {23},
  year         = {2017},
}