Pathogenic Germline Variants in 10,389 Adult Cancers.
Pathogenic Germline Variants in 10,389 Adult Cancers.
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DOI：
10.1016/j.cell.2018.03.039
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发表时间：
2018-04-05
期刊：
影响因子：
64.5
通讯作者：
Ding L
中科院分区：
文献类型：
--
作者：
Huang KL;Mashl RJ;Wu Y;Ritter DI;Wang J;Oh C;Paczkowska M;Reynolds S;Wyczalkowski MA;Oak N;Scott AD;Krassowski M;Cherniack AD;Houlahan KE;Jayasinghe R;Wang LB;Zhou DC;Liu D;Cao S;Kim YW;Koire A;McMichael JF;Hucthagowder V;Kim TB;Hahn A;Wang C;McLellan MD;Al-Mulla F;Johnson KJ;Cancer Genome Atlas Research Network;Lichtarge O;Boutros PC;Raphael B;Lazar AJ;Zhang W;Wendl MC;Govindan R;Jain S;Wheeler D;Kulkarni S;Dipersio JF;Reimand J;Meric-Bernstam F;Chen K;Shmulevich I;Plon SE;Chen F;Ding L
我们进行了迄今为止最大规模的癌症易感性变异研究，在33种癌症类型的10，389例病例中的8%中发现了853种致病或可能致病的变异。21个基因显示出单一或跨癌症关联，包括黑色素瘤中SDHA和胃腺癌中PALB 2的新关联。659个易感性变异和18个额外的肿瘤抑制基因大缺失，包括ATM，BRCA 1和NF 1，显示出低基因表达和频繁（43%）的杂合性丢失/双等位基因两次击中事件。我们还在癌基因中发现了33个这样的变异，包括与高基因表达相关的MET，RET，PTPN 11的错义。我们从优先的VUS中提名了47个额外的易感变异，这些变异得到了多个证据的支持，这些证据包括病例对照频率、杂合性丢失、表达效应以及与突变和修饰残基的共定位。我们的综合方法将罕见的易感性变异与功能性后果联系起来，为癌症中变异分类和生殖系基因检测的未来指南提供信息。
We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1 and NF1, showed low gene expression and frequent (43%) loss of heterozygosity/biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
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影响因子：
5.3
作者：
Chatterjee, Rajshekhar;Ramos, Enrique;Hoffman, Mary;VanWinkle, Jessica;Martin, Daniel R.;Davis, Thomas K.;Hoshi, Masato;Hmiel, Stanley P.;Beck, Anne;Hruska, Keith;Coplen, Doug;Liapis, Helen;Mitra, Robi;Druley, Todd;Austin, Paul;Jain, Sanjay
通讯作者：
Jain, Sanjay
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
通过对实体瘤的深层测序增强了临床可行性。
影响因子：
9.3
作者：
Chen K;Meric-Bernstam F;Zhao H;Zhang Q;Ezzeddine N;Tang LY;Qi Y;Mao Y;Chen T;Chong Z;Zhou W;Zheng X;Johnson A;Aldape KD;Routbort MJ;Luthra R;Kopetz S;Davies MA;de Groot J;Moulder S;Vinod R;Farhangfar CJ;Shaw KM;Mendelsohn J;Mills GB;Eterovic AK
通讯作者：
Eterovic AK
影响因子：
2.7
作者：
Cheng DT;Prasad M;Chekaluk Y;Benayed R;Sadowska J;Zehir A;Syed A;Wang YE;Somar J;Li Y;Yelskaya Z;Wong D;Robson ME;Offit K;Berger MF;Nafa K;Ladanyi M;Zhang L
通讯作者：
Zhang L
影响因子：
14.9
作者：
Hornbeck PV;Zhang B;Murray B;Kornhauser JM;Latham V;Skrzypek E
通讯作者：
Skrzypek E