分子分型新模型HRDetect:22%的乳腺癌有BRCA1/2基因功能缺陷,PARP抑制剂前景广阔
创作:FU 审核:萝卜医生 2017年05月14日
  • 1%-5%的乳腺癌患者携带BRCA1/2 生殖细胞基因突变,PARP抑制剂是可能的治疗选择;因此,寻找能预测BRCA1/2 基因功能缺陷的方法,十分重要;
  • 本研究基于BRCA1/2基因功能缺陷的分子特点,开发了一种全新的预测模型—HRDetect;
  • HRDetect预测BRCA1/2基因功能缺陷的敏感性是98.7%,曲线下面积(AUC)=0.98;
  • 利用该方法对独立的大规模乳腺癌标本进行检测:BRCA1/2基因功能缺陷的比例高达22%,这群人或许是PARP抑制剂的潜在获益人群。
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Nature Medicine [IF:36.13]

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

Nature Medicine:HRDetect是一种基于突变特征预测BRCA1和BRCA2缺失的方法

10.1038/nm.4292

2017-03-13, Other

Abstract & Authors:展开

Abstract:收起
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.

First Authors:
Helen Davies,Dominik Glodzik

Correspondence Authors:
Serena Nik-Zainal

All Authors:
Helen Davies,Dominik Glodzik,Sandro Morganella,Lucy R Yates,Johan Staaf,Xueqing Zou,Manasa Ramakrishna,Sancha Martin,Sandrine Boyault,Anieta M Sieuwerts,Peter T Simpson,Tari A King,Keiran Raine,Jorunn E Eyfjord,Gu Kong,Åke Borg,Ewan Birney,Hendrik G Stunnenberg,Marc J van de Vijver,Anne-Lise Børresen-Dale,John W M Martens,Paul N Span,Sunil R Lakhani,Anne Vincent-Salomon,Christos Sotiriou,Andrew Tutt,Alastair M Thompson,Steven Van Laere,Andrea L Richardson,Alain Viari,Peter J Campbell,Michael R Stratton,Serena Nik-Zainal

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