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

被引：770

作者：

Davies, Helen ^{[1
]}

Glodzik, Dominik ^{[1
]}

Morganella, Sandro ^{[1
]}

Yates, Lucy R. ^{[1
,2
]}

Staaf, Johan ^{[3
]}

Zou, Xueqing ^{[1
]}

Ramakrishna, Manasa ^{[1
,4
]}

Martin, Sancha ^{[1
]}

Boyault, Sandrine ^{[5
]}

Sieuwerts, Anieta M. ^{[6
]}

Simpson, Peter T. ^{[7
,8
]}

King, Tari A. ^{[9
]}

Raine, Keiran ^{[1
]}

Eyfjord, Jorunn E. ^{[10
]}

Kong, Gu ^{[11
]}

Borg, Ake

Birney, Ewan ^{[1
,12
]}

Stunnenberg, Hendrik G. ^{[13
]}

van de Vijver, Marc J. ^{[14
]}

Borresen-Dale, Anne-Lise ^{[15
,16
]}

Martens, John W. M. ^{[6
]}

Span, Paul N. ^{[17
,18
]}

Lakhani, Sunil R. ^{[7
,19
]}

Vincent-Salomon, Anne ^{[20
,21
]}

Sotiriou, Christos ^{[22
]}

Tutt, Andrew ^{[23
,24
]}

Thompson, Alastair M. ^{[25
]}

Van Laere, Steven ^{[26
,27
]}

Richardson, Andrea L. ^{[28
,29
]}

Viari, Alain ^{[30
,31
]}

Campbell, Peter J. ^{[1
]}

Stratton, Michael R. ^{[1
]}

Nik-Zainal, Serena ^{[1
,32
]}

机构：

[1] Wellcome Trust Sanger Inst, Hinxton, England

[2] Guys & St Thomas NHS Trust, London, England

[3] Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden

[4] AstraZeneca, Oncol, Innovat Med & Early Dev Biotech Unit, Saffron Walden, England

[5] Ctr Leon Berard, Translat Res Lab Dept, Lyon, France

[6] Erasmus Univ, Med Ctr, Erasmus MC Canc Inst & Canc Genom, Dept Med Oncol, Rotterdam, Netherlands

[7] Univ Queensland, Ctr Clin Res, Brisbane, Qld, Australia

[8] Univ Queensland, Sch Med, Brisbane, Qld, Australia

[9] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[10] Univ Iceland, Canc Res Lab, Fac Med, Reykjavik, Iceland

[11] Hanyang Univ, Coll Med, Dept Pathol, Seoul, South Korea

[12] European Bioinformat Inst, Mol Biol Lab, Wellcome Trust Genome Campus, Hinxton, Belgium

[13] Radboud Univ Nijmegen, Fac Sci & Med, Dept Mol Biol, Nijmegen, Netherlands

[14] Acad Med Ctr, Dept Pathol, Amsterdam, Netherlands

[15] Oslo Univ Hosp, Inst Canc Res, Norwegian Radium Hosp, Dept Canc Genet, Oslo, Norway

[16] Univ Oslo, KG Jebsen Ctr Breast Canc Res, Inst Clin Med, Oslo, Norway

[17] Radboud Univ Nijmegen, Dept Radiat Oncol, Med Ctr, Nijmegen, Netherlands

[18] Radboud Univ Nijmegen, Dept Lab Med, Med Ctr, Nijmegen, Netherlands

[19] Royal Brisbane & Womens Hosp, Pathol Queensland, Brisbane, Qld, Australia

[20] Inst Curie, Dept Pathol, Paris, France

[21] Inst Curie, INSERM U934, Paris, France

[22] Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab, Brussels, Belgium

[23] Kings Coll London, Breast Canc Now Res Unit, London, England

[24] Breast Canc Now Toby Robins Res Ctr, Inst Canc Res, London, England

[25] Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX 77030 USA

[26] Univ Antwerp, Canc Res Unit, Oncol Res Ctr, Fac Med & Hlth Sci, Antwerp, Belgium

[27] HistoGeneX, Antwerp, Belgium

[28] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[29] Dana Farber Canc Inst, Boston, MA 02115 USA

[30] INRIA Grenoble Rhone Alpes, Equipe Erable, Montbonnot St Martin, France

[31] Synergie Lyon Canc, Ctr Lyon Berard, Lyon, France

[32] Cambridge Univ Hosp NHS Fdn Trust, East Anglian Med Genet Serv, Cambridge, England

来源：

NATURE MEDICINE | 2017年 / 23卷 / 04期

基金：

欧盟第七框架计划; 英国惠康基金; 新加坡国家研究基金会;

关键词：

COPY NUMBER ANALYSIS; BREAST-CANCER; REPAIR DEFECTS; CHEMOTHERAPY; PREVALENCE; RESISTANCE; LANDSCAPE; OLAPARIB; THERAPY; GENOMES;

D O I：

10.1038/nm.4292

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：517 / +

页数：12

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