Journal Article

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

Sougnez, Carrie, Bandla, Santhoshi, Pennathur, Arjun, Bass, Adam J, Lander, Eric S, Shefler, Erica, Thompson, Kristin, Golub, Todd R, Peng, Shouyong, McKenna, Aaron, Imamura, Yu, Lin, Lin, Ogino, Shuji, Godfrey, Tony E, Lin, Jules, Reddy, Rishindra, Auclair, Daniel, Onofrio, Robert C, Sivachenko, Andrey, Beer, David G, Guiducci, Candace, Saksena, Gordon, Stewart, Chip, Carter, Scott L, Luketich, James D, Landrenau, Rodney, Cibulskis, Kristian, Voet, Douglas, Beroukhim, Rameen, Gabriel, Stacey B, Zhou, Zhongren, Chang, Andrew, Schumacher, Steven E, Lawrence, Michael S, Fox, Cameron, Dulak, Austin M, Ramos, Alex H, Getz, Gad, Stojanov, Petar

2013

Overview

Adam Bass, Gad Getz and colleagues report whole-exome sequencing of 149 esophageal adenocarcinomas (EACs) and whole-genome sequencing of 15 EACs. They identify a mutational signature defined by a high prevalence of A>C transversions, as well as 26 genes mutated at high frequency in EACs. The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/212 / 631/208/68 / 631/208/737 / 631/67/1504/1477 / Adenocarcinoma - genetics / Agriculture / Analysis / Animal Genetics and Genomics / Biomarkers, Tumor - genetics / Biomedicine / Cancer / Cancer Research / Cancer therapies / Care and treatment / Chromosome Mapping / DNA sequencing / Esophageal cancer / Esophageal Neoplasms - genetics / Exome - genetics / Gene Function / Gene mutations / Gene Rearrangement / Genetic aspects / Genetics / Genome, Human - genetics / Genomes / Grants / Health aspects / High-Throughput Nucleotide Sequencing / Human Genetics / Humans / Medical research / Methods / Mutation / Mutation - genetics / Neoplasm Invasiveness / Nucleotide sequencing / Physiological aspects / Risk factors / Signal transduction / Statistical analysis / Survival / Tumor proteins