Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

被引:598
作者
Dulak, Austin M. [1 ,2 ,3 ]
Stojanov, Petar [1 ,2 ,3 ]
Peng, Shouyong [1 ,2 ]
Lawrence, Michael S. [2 ]
Fox, Cameron [1 ]
Stewart, Chip [2 ]
Bandla, Santhoshi [4 ]
Imamura, Yu [1 ]
Schumacher, Steven E. [1 ,2 ]
Shefler, Erica [2 ]
McKenna, Aaron [2 ]
Carter, Scott L. [2 ]
Cibulskis, Kristian [2 ]
Sivachenko, Andrey [2 ]
Saksena, Gordon [2 ]
Voet, Douglas [2 ]
Ramos, Alex H. [2 ]
Auclair, Daniel [2 ]
Thompson, Kristin [2 ]
Sougnez, Carrie [2 ]
Onofrio, Robert C. [2 ]
Guiducci, Candace [2 ]
Beroukhim, Rameen [1 ,2 ,5 ,6 ]
Zhou, Zhongren [4 ]
Lin, Lin [7 ]
Lin, Jules [7 ]
Reddy, Rishindra [7 ]
Chang, Andrew [7 ]
Landrenau, Rodney [8 ]
Pennathur, Arjun [8 ]
Ogino, Shuji [1 ,6 ,9 ,10 ]
Luketich, James D. [8 ]
Golub, Todd R. [1 ,2 ,6 ,11 ]
Gabriel, Stacey B. [2 ]
Lander, Eric S. [2 ,3 ,6 ]
Beer, David G. [7 ]
Godfrey, Tony E. [4 ]
Getz, Gad [2 ,12 ,13 ]
Bass, Adam J. [1 ,2 ,5 ,6 ]
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[2] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA USA
[3] MIT, Dept Biol, Cambridge, MA USA
[4] Univ Rochester, Dept Surg, Rochester, NY USA
[5] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[7] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA
[8] Univ Pittsburgh, Med Ctr, Dept Cardiothorac Surg, Pittsburgh, PA USA
[9] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA
[10] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[11] Howard Hughes Med Inst, Chevy Chase, MD USA
[12] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA
[13] Dept Pathol, Boston, MA USA
基金
美国国家卫生研究院;
关键词
ERBB2 KINASE DOMAIN; SOMATIC MUTATIONS; GENE-MUTATIONS; BARRETT-ESOPHAGUS; STRUCTURAL BASIS; TROYER-SYNDROME; RAC ACTIVATION; CELL-ADHESION; LUNG-CANCER; EXPRESSION;
D O I
10.1038/ng.2591
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of similar to 15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.
引用
收藏
页码:478 / U37
页数:11
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