Genomic Determinants of Homologous Recombination Deficiency across Human Cancers.
Genomic Determinants of Homologous Recombination Deficiency across Human Cancers.
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人类癌症中同源异型增生缺陷的基因组决定因素。
DOI：
10.3390/cancers13184572
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发表时间：
2021-09-12
期刊：
影响因子：
5.2
通讯作者：
Huang KL
中科院分区：
文献类型：
--
作者：
Qing T;Wang X;Jun T;Ding L;Pusztai L;Huang KL
乳腺癌、卵巢癌、前列腺癌和胰腺癌中具有同源重组缺陷（HRD）的肿瘤对聚ADP核糖聚合酶抑制剂（PARPi）治疗有反应。然而，除了少数已知的致病性变异（包括影响BRCA 1/2的变异）外，尚不清楚其他哪些基因组事件会导致HRD。我们的研究系统地检查了超过9000种癌症的生殖细胞和体细胞基因组。我们鉴定了与HRD相关的改变，包括ATM和ATR基因突变;胃癌、膀胱癌和肺癌的特异性缺失;以及BRCA野生型乳腺癌、卵巢癌和胰腺癌。这些发现表明PARPi对具有广泛基因组改变的癌症具有潜在的更广泛的用途。与HRD相关的生殖系BRCA 1/2突变是乳腺癌、卵巢癌、胰腺癌和前列腺癌对聚ADP核糖聚合酶抑制剂（PARPi）治疗敏感性的临床生物标志物。然而，目前尚不清楚其他突变是否也可能导致HRD和PARPi在更广泛的癌症类型中的敏感性。我们的目标是确定与HRD表型相关的种系或体细胞改变，从而可能赋予PARPi敏感性。使用来自代表32种癌症类型的9000多个肿瘤的生殖系和体细胞基因组数据，我们检查了HRD评分与致病性生殖系变异、体细胞驱动突变和30个参与同源重组的候选基因的拷贝数缺失之间的关联。我们鉴定了几种种系和体细胞突变（例如，BRCA 1/2、PALB 2、ATM和ATR突变）与卵巢癌、乳腺癌、胰腺癌、胃癌、膀胱癌和肺癌中HRD表型相关。生殖系BRCA 1变异和体细胞TP 53突变的共同发生与乳腺癌中HRD的增加显著相关。值得注意的是，我们还鉴定了与HRD相关的多体细胞拷贝数缺失。我们的研究表明，多种癌症类型包括显示HRD表型的肿瘤亚组，并且应该在PARPi的未来临床研究和利用HRD的合成致死策略中考虑，这可能是由大量基因组改变引起的。
Tumors with homologous recombination deficiency (HRD) respond to Poly-ADP ribose polymerase inhibitor (PARPi) therapy in breast, ovarian, prostate, and pancreatic cancers. However, in addition to a handful of known pathogenic variants including those affecting BRCA1/2, it remains unclear what other genomic events can cause HRD. Our study systematically examined the germline and somatic genome of over 9000 cancers. We identified alterations associated with HRD, including mutations in ATM and ATR genes; specific deletions in stomach, bladder, and lung cancer; and BRCA-wild type breast, ovarian, and pancreatic cancers. These findings suggest a potentially broader utility for PARPi for cancers harboring a wide range of genomic alterations. Germline BRCA1/2 mutations associated with HRD are clinical biomarkers for sensitivity to poly-ADP ribose polymerase inhibitors (PARPi) treatment in breast, ovarian, pancreatic, and prostate cancers. However, it remains unclear whether other mutations may also lead to HRD and PARPi sensitivity across a broader range of cancer types. Our goal was to determine the germline or somatic alterations associated with the HRD phenotype that might therefore confer PARPi sensitivity. Using germline and somatic genomic data from over 9000 tumors representing 32 cancer types, we examined associations between HRD scores and pathogenic germline variants, somatic driver mutations, and copy number deletions in 30 candidate genes involved in homologous recombination. We identified several germline and somatic mutations (e.g., BRCA1/2, PALB2, ATM, and ATR mutations) associated with HRD phenotype in ovarian, breast, pancreatic, stomach, bladder, and lung cancer. The co-occurrence of germline BRCA1 variants and somatic TP53 mutations was significantly associated with increasing HRD in breast cancer. Notably, we also identified multiple somatic copy number deletions associated with HRD. Our study suggests that multiple cancer types include tumor subsets that show HRD phenotype and should be considered in the future clinical studies of PARPi and synthetic lethality strategies exploiting HRD, which can be caused by a large number of genomic alterations.
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实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
影响因子：
50.3
作者：
Carrot-Zhang, Jian;Chambwe, Nyasha;Beroukhim, Rameen
通讯作者：
Beroukhim, Rameen
影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
11.2
作者：
McCabe, Nuala;Turner, Nicholas C.;Ashworth, Alan
通讯作者：
Ashworth, Alan
影响因子：
11.2
作者：
Popova, Tatiana;Manie, Elodie;Stern, Marc-Henri
通讯作者：
Stern, Marc-Henri