Endometrial Carcinoma — TCGA (2013)

Overview

The Cancer Genome Atlas integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas (307 endometrioid, 53 serous, 13 mixed histology), published in Nature 2013. The study proposed a four-category molecular classification that refines histology-based subtyping and may guide post-surgical adjuvant therapy decisions. PMID:23636398

Composition

  • 373 endometrial carcinomas with matched germline DNA: 307 endometrioid, 53 serous, and 13 mixed-histology cases; median follow-up 32 months (range 1–195 months); 21% recurred and 11% died at time of analysis. PMID:23636398
  • Cancer types: UCEC (uterine endometrioid carcinoma), UEC, and USC (uterine serous carcinoma). PMID:23636398
  • Whole-exome sequencing performed on 248 tumor/normal pairs (≥20× depth); low-pass paired-end whole-genome sequencing on 106–107 tumors (mean depth 6×); MSI testing on all samples using seven repeat loci. PMID:23636398

Assays / panels (linked)

Papers using this cohort

  • PMID:23636398 — The Cancer Genome Atlas Research Network, “Integrated genomic characterization of endometrial carcinoma,” Nature 2013.

Notable findings derived from this cohort

  • Four integrated molecular subgroups: POLE ultramutated (n=17, ~7%; 232×10⁻⁶ mut/Mb), MSI hypermutated (n=65; 18×10⁻⁶ mut/Mb), copy-number low endometrioid (n=90; 2.9×10⁻⁶ mut/Mb), and copy-number high serous-like (n=60; 2.3×10⁻⁶ mut/Mb). PMID:23636398
  • POLE exonuclease-domain hotspots Pro286Arg and Val411Leu define the ultramutated subgroup (100% mutated, Q=4.2×10⁻²³) and are associated with significantly better progression-free survival (log-rank P=0.02). PMID:23636398
  • Copy-number high (serous-like) tumors share molecular features with high-grade serous ovarian carcinoma and basal-like breast carcinoma: TP53 mutations (~90–91%), extensive SCNAs, focal amplifications of MYC, ERBB2, CCNE1, FGFR3, and SOX17, and significantly worse progression-free survival (log-rank P=0.003). PMID:23636398
  • 93% of endometrioid tumors harbored PI(3)K/AKT pathway alterations; PTEN mutated in 84% of MSS endometrioid and 94% of POLE-ultramutated; CTNNB1 mutated in 52% of copy-number-low MSS endometrioid. PMID:23636398
  • Novel recurrently mutated gene ARID5B (SWI/SNF-related ARID-family chromatin remodeller) identified: 23.1% MSI vs. 5.6% MSS endometrioid vs. 0% serous. RPL22 frameshift indels almost exclusively in the MSI group (36.9%). PMID:23636398
  • MEMo identified a mutually exclusive WNT-axis module of CTNNB1, KRAS, and SOX17 in copy-number-low tumors; novel recurrent SOX17 mutations at Ala96Gly and Ser403Ile (8% in this subgroup). PMID:23636398
  • Low-pass WGS on 106 tumors found recurrent translocations involving BCL family members (BCL2, BCL7A, BCL9, BCL2L11) in 5/106 cases, all predicted in-frame. PMID:23636398

Sources

  • DOI: 10.1038/nature12113

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