You are here

Nat Genet DOI:10.1038/ng.2591

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

Publication TypeJournal Article
Year of Publication2013
AuthorsDulak, AM, Stojanov, P, Peng, S, Lawrence, MS, Fox, C, Stewart, C, Bandla, S, Imamura, Y, Schumacher, SE, Shefler, E, McKenna, A, Carter, SL, Cibulskis, K, Sivachenko, A, Saksena, G, Voet, D, Ramos, AH, Auclair, D, Thompson, K, Sougnez, C, Onofrio, RC, Guiducci, C, Beroukhim, R, Zhou, Z, Lin, L, Lin, J, Reddy, R, Chang, A, Landrenau, R, Pennathur, A, Ogino, S, Luketich, JD, Golub, TR, Gabriel, SB, Lander, ES, Beer, DG, Godfrey, TE, Getz, G, Bass, AJ
JournalNat Genet
Date Published2013 May
KeywordsAdenocarcinoma, Biomarkers, Tumor, Chromosome Mapping, Esophageal Neoplasms, Exome, Gene Rearrangement, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Mutation, Neoplasm Invasiveness

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.


Alternate JournalNat. Genet.
PubMed ID23525077
PubMed Central IDPMC3678719
Grant ListU54 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