TCGA Esophageal and Stomach Cancers (STES, Nature 2017)

Overview

The stes_tcga_pub dataset is the combined esophageal-stomach TCGA publication cohort, produced by the TCGA Research Network through integrated multi-platform molecular profiling of oesophageal carcinomas (n=164: 90 ESCC, 72 EAC, 2 undifferentiated) alongside 359 gastric adenocarcinomas and 36 gastroesophageal-junction (GEJ) adenocarcinomas. The study incorporated 77 additional STADs not present in the prior stad_tcga_pub analysis. Published in Nature (2017), the dataset was specifically assembled to compare oesophageal squamous cell carcinoma (ESCC) with oesophageal adenocarcinoma (ESCA/EAC) and gastric adenocarcinoma (STAD), demonstrating that EAC is molecularly indistinguishable from chromosomally-unstable gastric cancer.

Composition

• 164 oesophageal carcinomas: 90 ESCC, 72 EAC (ESCA; 61 definite + 11 probable), 2 undifferentiated.
• 359 gastric adenocarcinomas (STAD) as comparator (including 77 STADs not in original stad_tcga_pub).
• 36 GEJ adenocarcinomas of indeterminate origin.
• Total: 559 samples across esophagus, GEJ, and stomach.
• Geographic distribution of ESCC: Vietnamese patients (n=41), Eastern European, South American, and US/Canadian patients.
• 322 oesophageal cases submitted to the BCR; 185 qualified by pathology/molecular QC; 171 entered genomic analysis after expert re-review.

Assays / panels (linked)

• whole-exome sequencing — Agilent SureSelect Human All Exon V5 (Broad Institute, STAD-labelled) or Nimblegen SeqCap EZ Human Exome Library v3.0 + custom IDT viral probes (Washington University, ESCA-labelled).
• Low-pass (6–8×) whole-genome sequencing on 51 oesophageal cancers.
• SNP-array copy-number profiling on Affymetrix SNP 6.0.
• DNA methylation on Illumina HumanMethylation450 (HM450).
• mRNA-seq and miRNA-seq.
• Reverse-phase protein array (RPPA) on 113 tumors.
• Integrative clustering via iCluster; significantly mutated genes by MutSigCV2.0; recurrent SCNAs by GISTIC 2.0; allelic copy number/purity/ploidy by ABSOLUTE; mutation signatures by Bayesian NMF.

Papers using this cohort

• PMID:28052061 — TCGA Research Network 2017. Comprehensive molecular characterization of 164 oesophageal carcinomas compared to 395 gastroesophageal adenocarcinomas; established molecular distinctness of ESCC vs EAC, three ESCC molecular subtypes, and molecular equivalence of EAC with CIN gastric cancer.

Notable findings derived from this cohort

• EAC and ESCC are molecularly distinct across all platforms: ESCC resembles squamous carcinomas of head/neck and lung, while EAC is indistinguishable from chromosomally-unstable (CIN) gastric adenocarcinoma PMID:28052061.
• Three ESCC molecular subtypes defined: ESCC1 (NRF2-pathway/classical squamous; NFE2L2, KEAP1, SOX2/TP63 amplification); ESCC2 (NOTCH/PI3K/immune-infiltrated; NOTCH1, CDK6 amplification); ESCC3 (PI3K-activated/SMARCA4/KMT2D mutant, US/Canada-restricted) PMID:28052061.
• Significantly mutated genes — ESCC: TP53, NFE2L2, KMT2D, ZNF750, NOTCH1, TGFBR2. Significantly mutated genes — EAC: TP53, CDKN2A, ARID1A, SMAD4, ERBB2 PMID:28052061.
• ERBB2 altered in 32% of EACs vs 3% of ESCCs; CCND1 amplified in 57% of ESCC vs 15% of EAC; CDKN2A inactivated in 76% of both histologies PMID:28052061.
• No aetiological role for HPV in ESCC; HPV-transcript levels resembled HPV-negative HNSCC PMID:28052061.
• APOBEC mutation signatures enriched in ESCC vs EAC (p=5e-5); NFE2L2 mutations enriched in Vietnamese ESCC patients (24% vs 6% in others, p=0.017) PMID:28052061.
• 71/72 EACs classified as CIN per TCGA gastric subtyping; integrative clustering showed no separation between EAC and CIN gastric tumors — supporting treatment as a single disease entity PMID:28052061.

Sources

• cBioPortal study: stes_tcga_pub
• Published: TCGA Research Network, Nature 2017.

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