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

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 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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Davies H,Glodzik D,Morganella S,Yates LR,Staaf J,Zou X,Ramakrishna M,Martin S,Boyault S,Sieuwerts AM,Simpson PT,King TA,Raine K,Eyfjord JE,Kong G,Borg Å,Birney E,Stunnenberg HG,van de Vijver MJ,Børresen-Dale AL,Ma

doi

10.1038/nm.4292

subject

Has Abstract

pub_date

2017-04-01 00:00:00

pages

517-525

issue

4

eissn

1078-8956

issn

1546-170X

pii

nm.4292

journal_volume

23

pub_type

杂志文章

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