title: Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Austin M
authors.initials: AM
authors.lastname: Dulak
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.forename: Shouyong
authors.initials: S
authors.lastname: Peng
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Cameron
authors.initials: C
authors.lastname: Fox
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.forename: Santhoshi
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authors.lastname: Bandla
authors.forename: Yu
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authors.lastname: Imamura
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.forename: Erica
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authors.lastname: Shefler
authors.forename: Aaron
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authors.lastname: McKenna
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.forename: Gordon
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authors.lastname: Saksena
authors.forename: Douglas
authors.initials: D
authors.lastname: Voet
authors.forename: Alex H
authors.initials: AH
authors.lastname: Ramos
authors.forename: Daniel
authors.initials: D
authors.lastname: Auclair
authors.forename: Kristin
authors.initials: K
authors.lastname: Thompson
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Robert C
authors.initials: RC
authors.lastname: Onofrio
authors.forename: Candace
authors.initials: C
authors.lastname: Guiducci
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Zhongren
authors.initials: Z
authors.lastname: Zhou
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Jules
authors.initials: J
authors.lastname: Lin
authors.forename: Rishindra
authors.initials: R
authors.lastname: Reddy
authors.forename: Andrew
authors.initials: A
authors.lastname: Chang
authors.forename: Rodney
authors.initials: R
authors.lastname: Landrenau
authors.forename: Arjun
authors.initials: A
authors.lastname: Pennathur
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: James D
authors.initials: JD
authors.lastname: Luketich
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Tony E
authors.initials: TE
authors.lastname: Godfrey
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002874:Chromosome Mapping; D004938:Esophageal Neoplasms / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D015321:Gene Rearrangement; D015894:Genome, Human / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness
chemical_list: D014408:Biomarkers, Tumor