Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.
Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.
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DOI：
10.1038/ng.3013
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发表时间：
2014-08
期刊：
影响因子：
30.8
通讯作者：
Fitzgerald, Rebecca C.
中科院分区：
文献类型：
--
作者：
Weaver, Jamie M. J.;Ross-Innes, Caryn S.;Shannon, Nicholas;Lynch, Andy G.;Forshew, Tim;Barbera, Mariagnese;Murtaza, Muhammed;Ong, Chin-Ann J.;Lao-Sirieix, Pierre;Dunning, Mark J.;Smith, Laura;Smith, Mike L.;Anderson, Charlotte L.;Carvalho, Benilton;O'Donovan, Maria;Underwood, Timothy J.;May, Andrew P.;Grehan, Nicola;Hardwick, Richard;Davies, Jim;Oloumi, Arusha;Aparicio, Sam;Caldas, Carlos;Eldridge, Matthew D.;Edwards, Paul A. W.;Rosenfeld, Nitzan;Tavare, Simon;Fitzgerald, Rebecca C.
癌症基因组测序研究已经确定了许多驱动基因，但致癌突变的相对时间仍不清楚。从癌前巴雷特食管到食管腺癌（EAC）的逐渐进展为研究体细胞突变的顺序提供了一个理想的模型。我们使用 112 个 EAC 的全基因组测序和扩增子重测序鉴定了反复突变的基因并评估了克隆结构。接下来，我们从恶性肿瘤发展的两个关键转变点筛选了 109 份活检样本；良性化生非发育不良 Barrett 食管 (NDBE，n=66) 和高度发育不良 (HGD，n=43)。出乎意料的是，EAC 中大多数经常突变的基因也在 NDBE 中发生了突变。只有 TP53 和 SMAD4 具有阶段特异性，分别局限于 HGD 和 EAC。最后，我们应用这些知识在新型非内窥镜测试中识别高风险巴雷特食管。总之，EAC 驱动基因的突变通常发生在疾病发展的早期，对诊断和治疗策略具有深远的影响。
Cancer genome sequencing studies have identified numerous driver genes but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from pre-malignant Barrett’s esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently-mutated genes and assessed clonal structure using whole-genome sequencing and amplicon-resequencing of 112 EACs. We next screened a cohort of 109 biopsies from two key transition points in the development of malignancy; benign metaplastic never-dysplastic Barrett’s esophagus (NDBE, n=66), and high-grade dysplasia (HGD, n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 were stage-specific, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett’s esophagus in a novel non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.
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影响因子：
24.5
作者：
Goh, X. Y.;Rees, J. R. E.;Fitzgerald, R. C.
通讯作者：
Fitzgerald, R. C.
影响因子：
50.3
作者：
Quante M;Bhagat G;Abrams JA;Marache F;Good P;Lee MD;Lee Y;Friedman R;Asfaha S;Dubeykovskaya Z;Mahmood U;Figueiredo JL;Kitajewski J;Shawber C;Lightdale CJ;Rustgi AK;Wang TC
通讯作者：
Wang TC
影响因子：
30.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
64.5
作者：
Nik-Zainal S;Van Loo P;Wedge DC;Alexandrov LB;Greenman CD;Lau KW;Raine K;Jones D;Marshall J;Ramakrishna M;Shlien A;Cooke SL;Hinton J;Menzies A;Stebbings LA;Leroy C;Jia M;Rance R;Mudie LJ;Gamble SJ;Stephens PJ;McLaren S;Tarpey PS;Papaemmanuil E;Davies HR;Varela I;McBride DJ;Bignell GR;Leung K;Butler AP;Teague JW;Martin S;Jönsson G;Mariani O;Boyault S;Miron P;Fatima A;Langerød A;Aparicio SA;Tutt A;Sieuwerts AM;Borg Å;Thomas G;Salomon AV;Richardson AL;Børresen-Dale AL;Futreal PA;Stratton MR;Campbell PJ;Breast Cancer Working Group of the International Cancer Genome Consortium
通讯作者：
Breast Cancer Working Group of the International Cancer Genome Consortium