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

Nat Genet
Authors
Keywords
Abstract

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.

Year of Publication
2013
Journal
Nat Genet
Volume
45
Issue
5
Pages
478-86
Date Published
2013 May
ISSN
1546-1718
URL
DOI
10.1038/ng.2591
PubMed ID
23525077
PubMed Central ID
PMC3678719
Links
Grant list
U54 HG003067 / HG / NHGRI NIH HHS / United States
P30 CA046592 / CA / NCI NIH HHS / United States
U54 CA163059 / CA / NCI NIH HHS / United States
R01 CA151993 / CA / NCI NIH HHS / United States
K08 CA134931 / CA / NCI NIH HHS / United States
CA130853 / CA / NCI NIH HHS / United States
CA46592 / CA / NCI NIH HHS / United States
CA090665 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
P50 CA127003 / CA / NCI NIH HHS / United States
CA163059 / CA / NCI NIH HHS / United States