Esophageal Adenocarcinoma — Broad/Columbia (Dulak 2013)

Overview

Whole-exome and whole-genome sequencing study of 149 fresh-frozen, surgically-resected, treatment-naïve esophageal adenocarcinoma (EAC) and gastro-esophageal junction (GEJ) tumor/normal pairs from Dulak et al. (Nature Genetics 2013). Raw data deposited under dbGaP phs000598.v1.p1. PMID:23525077

Composition

  • 149 EAC/GEJ tumor/normal pairs subjected to whole-exome sequencing (SureSelect v2 Exome bait, Illumina HiSeq; mean coverage 83.3× tumor / 85.9× normal); 16 pairs additionally subjected to whole-genome sequencing (~49× tumor / 30× germline); 14 WGS samples additionally profiled on Affymetrix mRNA expression arrays (GEO GSE42363). PMID:23525077
  • Cancer types: ESCA (esophageal adenocarcinoma) and GEJ (gastric-esophageal junction adenocarcinoma). PMID:23525077
  • Four MSI-positive hypermutated tumors (mutation frequencies 14.6–50.9/Mb; MSH6 + MSH3 mutations) excluded from significance analysis, leaving 145 evaluable tumors. PMID:23525077

Assays / panels (linked)

Papers using this cohort

  • PMID:23525077 — Dulak et al., “Exome and whole genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity,” Nat Genet 2013.

Notable findings derived from this cohort

  • Median genome-wide mutation frequency 9.9/Mb (range 7.1–25.2/Mb), exceeded in solid tumors only by lung cancer and melanoma; median 104 non-silent coding mutations per tumor. PMID:23525077
  • A novel EAC-specific mutational signature dominated by A>C transversions at AA dinucleotides accounts for 29% of all genome-wide mutations; the signature shows transcription-coupled repair attenuation and strong enrichment at AAG trinucleotides (49.3/Mb). PMID:23525077
  • 26 significantly mutated genes (MutSig FDR q<0.1): confirmed TP53, CDKN2A, SMAD4, PIK3CA, ARID1A; novel candidates ELMO1, DOCK2, SPART, TLR4, SMARCA4, ARID2. PMID:23525077
  • ELMO1 or DOCK2 mutations in 25/145 (17%) of EACs; EAC-derived ELMO1 mutants augment NIH/3T3 invasion 2–7-fold over wild-type, implicating aberrant RAC1 signaling. PMID:23525077
  • SWI/SNF family members ARID1A, SMARCA4, ARID2 mutated in 20% of tumors; 24% of EACs harbored chromatin-modifying-factor mutations when including PBRM1 and JARID2. PMID:23525077
  • 23% of tumors had mutations in genes with approved/preclinical targeted agents; combined with copy-number amplification, 48% had a targetable alteration. PMID:23525077

Sources

  • dbGaP: phs000598.v1.p1
  • GEO: GSE42363 (Affymetrix expression arrays)
  • DOI: 10.1038/ng.2591

This page was processed by crosslinker on 2026-05-09.