Gastric Adenocarcinoma (TMUCIH, PNAS 2015)

Overview

Multi-tier sequencing cohort of gastric adenocarcinoma (GC) from the Tianjin Medical University Cancer Institute and Hospital (TMUCIH). Comprises a whole-exome sequencing discovery cohort (78 primary GCs with matched blood), a whole-genome sequencing sub-cohort (2 patients with multi-region tumor + lymph node samples), and a targeted resequencing validation cohort (216 additional GC cases). Total study population: 294 patients (after 5 excluded for discrepant pathology). All patients are treatment-naive northern Chinese adults; primary aims were to characterize the somatic landscape, define clonal heterogeneity subtypes, discover novel drivers in the ERBB and Wnt pathways, and validate findings against the TCGA STAD cohort. Sequence data deposited at EGA under accession EGAS00001001056.

Composition

  • Cancer type: Gastric adenocarcinoma (STAD)
  • Total patients: 294 (78 WES discovery + 216 targeted-seq validation; 2 WGS sub-cases)
  • Anatomic location: Antrum 64 (21.77%), body 118 (40.14%), cardia 112 (38.10%)
  • Histology: 124 intestinal-type, 152 diffuse-type, 18 mixed (Lauren classification)
  • Stage: I 6 (2.05%), II 85 (28.91%), III 97 (32.99%), IV 106 (36.05%)
  • Follow-up: Median 13.84 months overall; 25.08 months for WES series
  • Treatment: Treatment-naive; no prior chemotherapy or radiotherapy
  • Population: Northern Chinese; differences vs. Russian TCGA STAD cohort observed for anatomic-location mutation enrichments
  • Reference genome: hg19

Assays / panels (linked)

  • whole-exome-seq: 78 tumor/normal pairs on Illumina HiSeq 2000 with Agilent SureSelect capture; mean coverage 167× tumor / 170× normal; 85% of exons ≥20×
  • whole-genome-seq: 2 patients (Pt1, Pt2), each with 3 primary-tumor regions + 2 matched lymph-node metastases
  • targeted-dna-seq: 216-case validation cohort, 103 recurrent genes on the Ion Torrent PGM platform
  • mutsig: MutSigCV for significantly mutated gene discovery
  • phylogenetic-tree-reconstruction: multi-region phylogenetics for clonal evolution

Papers using this cohort

  • PMID:25583476 — Chen et al., PNAS 2015. “Genomic landscape of gastric cancer from a northern Chinese population.”

Notable findings derived from this cohort

  • SciClone clonality analysis identified a high-clonality (HiC, >4 clones, n=9) subtype with significantly shorter survival vs. low-clonality (LoC, ≤4 clones, n=68); HiC–survival association was an independent prognostic factor after multivariate adjustment (adjusted HR 4.69, 95% CI 1.62–13.6, P=0.0043) PMID:25583476.
  • NRG1 or ERBB4 mutations were detected in 34/294 (11.6%) of cases, with EGF-like domain clustering in NRG1 (p.A221T, p.A225P, p.E223G, p.R224Q, p.S226P) and kinase/receptor-domain mutations in ERBB4; ERBB/NRG family mutations were mutually exclusive (permutation P=0.02), defining a candidate lapatinib-targetable subset PMID:25583476.
  • BRCA2 mutations in 17/294 Tianjin cases (5.8%); pooling with TCGA STAD (28/289 cases) yielded log-rank P=0.03 survival benefit for BRCA2-mutant GC patients; adjusted HR 0.37 (95% CI 0.13–0.96, P=0.05), establishing BRCA2 as an independent prognostic marker PMID:25583476.
  • MutSigCV identified 16 significantly mutated genes (q<0.2) including TP53, ARID1A, CDH1, APC, RHOA, PIK3CA, SMAD4, MYC, and KRAS; TP53 was enriched in HiC and present only as minor subclones (<15% VAF), implying single-agent therapy could select for TP53-wild-type populations PMID:25583476.
  • Anatomic-location-specific mutation enrichments (antrum, body, cardia) were observed in this northern Chinese cohort but did not replicate in the Russian TCGA STAD cohort, suggesting population-specific or environmental contributions to mutational distribution PMID:25583476.

Sources

  • cBioPortal study: egc_tmucih_2015
  • EGA accession: EGAS00001001056
  • Citation: Chen et al. PNAS 2015 PMID:25583476

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