HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.
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DOI：
10.1038/nm.4292
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发表时间：
2017-04
期刊：
影响因子：
82.9
通讯作者：
Nik-Zainal S
中科院分区：
文献类型：
--
作者：
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;Martens JW;Span PN;Lakhani SR;Vincent-Salomon A;Sotiriou C;Tutt A;Thompson AM;Van Laere S;Richardson AL;Viari A;Campbell PJ;Stratton MR;Nik-Zainal S
大约1-5%的乳腺癌归因于BRCA 1或BRCA 2的遗传突变，并且对聚（ADP-核糖）聚合酶（PARP）抑制剂选择性敏感。其他癌症类型中BRCA 1/BRCA 2的生殖系和/或体细胞突变也赋予对PARP抑制剂的选择性敏感性。因此，人们一直在寻找检测BRCA 1/BRCA 2缺陷肿瘤的检测方法。最近，体细胞替代，插入/缺失和重排模式或突变签名与BRCA 1/BRCA 2功能障碍有关。我们使用监督套索逻辑回归模型来识别预测BRCA 1/BRCA 2缺陷的六个关键区别突变特征。开发了一种称为HRDetect的加权模型，用于准确检测BRCA 1/BRCA 2缺陷样本。HRDetect以98.7%的灵敏度（AUC 0.98）识别BRCA 1/BRCA 2缺陷肿瘤。将该模型应用于560例乳腺癌患者的队列中，其中有22例已知的生殖系BRCA 1/BRCA 2突变携带者，使我们能够识别出另外22例体细胞BRCA 1/BRCA 2无效肿瘤和47例未检测到突变的功能性BRCA 1/BRCA 2缺陷肿瘤。我们在乳腺癌、卵巢癌和胰腺癌的独立队列中验证了HRDetect，并证明了替代测序策略的有效性。因此，整合所有类别的突变特征揭示了对PARP抑制具有选择性治疗敏感性的乳腺癌患者比例（高达22%）比迄今为止估计的（约1-5%）更大。
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. Germline and/or somatic mutations in BRCA1/BRCA2 in other cancer types also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2 deficient tumours have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns or mutational signatures were associated with BRCA1/BRCA2 dysfunction. We used a supervised lasso logistic regression model to identify six critically 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 tumours with 98.7% sensitivity (AUC 0.98). Application of this model in a cohort of 560 breast cancer patients with 22 known germline BRCA1/BRCA2 mutation carriers, allowed us to identify an additional 22 somatic BRCA1/BRCA2 null tumours and 47 tumours with functional BRCA1/BRCA2-deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers, and demonstrate efficacy on alternative sequencing strategies. Integrating all classes of mutational signatures thus reveals a larger proportion of breast cancer patients (of up to 22%) than hitherto appreciated (~1-5%) that could have selective therapeutic sensitivity to PARP-inhibition.
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影响因子：
16.6
作者：
Morganella, Sandro;Alexandrov, Ludmil B.;Glodzik, Dominik;Zou, Xueqing;Davies, Helen;Staaf, Johan;Sieuwerts, Anieta M.;Brinkman, Arie B.;Martin, Sancha;Ramakrishna, Manasa;Butler, Adam;Kim, Hyung-Yong;Borg, Ake;Sotiriou, Christos;Futreal, P. Andrew;Campbell, Peter J.;Span, Paul N.;Van Laere, Steven;Lakhani, Sunil R.;Eyfjord, Jorunn E.;Thompson, Alastair M.;Stunnenberg, Hendrik G.;de Vijver, Marc J. van;Martens, John W. M.;Borresen-Dale, Anne-Lise;Richardson, Andrea L.;Kong, Gu;Thomas, Gilles;Sale, Julian;Rada, Cristina;Stratton, Michael R.;Birney, Ewan;Nik-Zainal, Serena
通讯作者：
Nik-Zainal, Serena
DOI：
10.1126/science.1251827
发表时间：
2014-03-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Couch FJ;Nathanson KL;Offit K
通讯作者：
Offit K
影响因子：
10.3
作者：
Jazaeri, AA;Yee, CJ;Liu, ET
通讯作者：
Liu, ET
影响因子：
64.8
作者：
Bailey, Peter;Chang, David K.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
影响因子：
3.8
作者：
Joosse, Simon A.;van Beers, Erik H.;Nederlof, Petra M.
通讯作者：
Nederlof, Petra M.