Uterine Endometrioid Carcinoma (UEC)

Overview

Uterine Endometrioid Carcinoma (UEC) is the most common histologic subtype of endometrial carcinoma, classified under the Endometrial Cancer main type in OncoTree (parent node UCEC). It is characterized by high PI3K/AKT pathway alteration rates (93%), frequent PTEN and CTNNB1 mutations in MSS/copy-number-low tumors, and a subset with POLE exonuclease-domain hotspot mutations that confer improved prognosis.

Cohorts in the corpus

  • ucec_tcga_pub — 307 endometrioid cases (among 373 total endometrial carcinomas) profiled by TCGA with WES (248 tumor/normal pairs), RNA-seq (333 tumors), RPPA (293), methylation 450k arrays (373), and low-pass WGS (106–107 tumors); 21% recurred, 11% died at time of analysis. PMID:23636398

Recurrent alterations

  • TCGA integrated analysis of 373 endometrial carcinomas (307 endometrioid, 53 serous, 13 mixed) proposed four molecular subgroups: POLE ultramutated (~7%, improved PFS), MSI hypermutated (~28%), copy-number low (CTNNB1-high), and copy-number high/serous-like (TP53 ~90%, worse PFS); 93% of endometrioid tumors had PI3K/AKT alterations PMID:23636398
  • PTEN mutated in 84% of MSS endometrioid tumors and 94% of POLE-ultramutated tumors (only 11% in serous-like). PMID:23636398
  • CTNNB1 mutated in 52% of copy-number-low MSS endometrioid tumors; mutually exclusive with KRAS and SOX17. PMID:23636398
  • POLE exonuclease-domain hotspots Pro286Arg and Val411Leu in 13/17 (76%) ultramutated samples; POLE-ultramutated subgroup associated with significantly better PFS (log-rank P=0.02). PMID:23636398
  • MSI detected in 40% of endometrioid tumors (vs. 2% of serous); MSI tumors had ~10× higher mutation frequency than MSS endometrioid tumors. PMID:23636398
  • ARID5B newly identified as recurrently mutated at 23.1% in MSI vs. 5.6% in MSS endometrioid vs. 0% in serous-like. PMID:23636398
  • Cross-histology analysis of 63 CCECs against 40 endometrioid carcinomas (UEC) showed: 82.5% of UEC had endometrioid-like molecular profiles (PTEN/KRAS/ARID1A/PIK3R1/PIK3CA mutations, MSI); POLE and MMR mutation signatures were enriched in endometrioid lineages per the four-subgroup TCGA UCEC framework referenced in this study. PMID:28485815

Subtypes

  • POLE ultramutated (~7%): 232 × 10⁻⁶ mut/Mb; hotspot POLE mutations; significantly improved PFS. PMID:23636398
  • MSI hypermutated (~28%): MLH1 promoter hypermethylation dominant mechanism; 18 × 10⁻⁶ mut/Mb; RPL22 frameshift indels in 36.9%. PMID:23636398
  • Copy-number low (~38%): CTNNB1-high (52%); 2.9 × 10⁻⁶ mut/Mb; increased PGR expression suggesting hormonal-therapy responsiveness. PMID:23636398
  • Copy-number high / serous-like (~25% of high-grade endometrioid): TP53 mutations (~90%); extensive SCNAs; molecular similarities to HGSOC and basal-like breast carcinoma; worse PFS (log-rank P=0.003 vs. endometrioid clusters). PMID:23636398

Therapeutic landscape

  • Authors argue ~25% of high-grade endometrioid tumors have a serous-like molecular phenotype and may benefit from chemotherapy (doxorubicin, cisplatin, paclitaxel) rather than adjuvant radiotherapy. PMID:23636398
  • PI3K/AKT pathway alteration in 93% of endometrioid tumors makes this the dominant targetable axis. PMID:23636398
  • Increased PGR expression in the copy-number-low cluster suggests hormonal-therapy responsiveness in this subgroup. PMID:23636398
  • POLE-mutant tumors’ improved PFS raises the possibility of de-escalation of adjuvant therapy. PMID:23636398

Sources

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

  • PMID:28485815

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