Endometrial Carcinoma (UCEC)

Overview

Endometrial carcinoma (UCEC) is the most common gynecologic malignancy in the United States. On OncoTree it is a child of UTERUS and the parent for uterine serous carcinoma (USC), uterine carcinosarcoma (UCS), and other subtypes. TCGA molecular subtypes — POLE-mutant, MSI-H/dMMR, CN-high/TP53abn, and CN-low/NSMP — have prognostic and therapeutic relevance.

Cohorts in the corpus

  • 1,882 prospectively sequenced endometrial carcinoma patients (259 self-identified Black, 1,623 White) at MSK (1/2014–12/2021) using MSK-IMPACT (341–505 gene panel). Dataset: ucec_ancestry_cds_msk_2023. PMID:37651310
  • 35 patients with recurrent/advanced dMMR/MSI-H or hypermutated endometrial or ovarian cancers enrolled in phase 2 nivolumab trial (NCT03241745). 83% endometrioid histology. Dataset: ucec_msk_2024. PMID:38653864

Recurrent alterations

  • TP53 — mutations in 72% of Black vs. 42% of White patients (q<0.001); defines the CN-H/TP53abn molecular subtype. PMID:37651310
  • PTEN — mutations in 26% Black vs. 55% White (q<0.001); associated with endometrioid histology. Mutated in 76% of dMMR/MSI-H cohort. PMID:37651310 PMID:38653864
  • PIK3CA — mutations in 38% Black vs. 46% White (similar frequency, different mechanism); mutated in 48% of dMMR/MSI-H cohort. PMID:37651310 PMID:38653864
  • CCNE1 — amplification enriched in Black patients (15% vs. 4%, q<0.001) and in carcinosarcomas (29% vs. 10%). PMID:37651310
  • ERBB2 — amplification enriched in Black patients (12% vs. 3%, q<0.001); therapeutic target for trastuzumab and T-DXd. PMID:37651310
  • ARID1A — mutations less frequent in Black patients (19% vs. 47%); mutated in 82% of dMMR/MSI-H cohort. PMID:37651310 PMID:38653864
  • MLH1 — promoter hypermethylation in 66% of dMMR/MSI-H cohort; somatic/germline mutations in 30%. PMID:38653864
  • SETD1B — mutations in 58% of nivolumab responders vs. 14% non-responders (P=0.015). PMID:38653864
  • MEGF8 — mutations in 32% of nivolumab responders vs. 0% non-responders (P=0.027). PMID:38653864
  • POLE — exonuclease domain mutations rare in Black patients (1.2% vs. 5.8%); favorable prognosis subtype. PMID:37651310
  • KMT2B — mutations enriched in CN-H/TP53abn ECs (16% vs. 8%) and carcinosarcomas (31% vs. 10%) from Black patients. PMID:37651310
  • 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
  • Endometrial polyps harbour low-VAF hotspot mutations in canonical UCEC driver genes (KRAS 26%, PIK3CA, PIK3R1, PTEN, ERBB2, FBXW7); KEGG pathway analysis flags ‘endometrial cancer’ as top enriched pathway (FDR p=2.8×10⁻⁵), supporting polyps as potential UCEC precursor lesions PMID:28445112
  • In the MSK-IMPACT pan-cancer cohort, ESR1 hotspot mutations were found in UCEC almost exclusively in post-hormone-therapy metastatic tumors; MSI UCEC patients showed responses to immune checkpoint blockade; POLE and MMR mutation signatures were enriched in endometrial lineages. PMID:28481359
  • Whole-exome sequencing of 63 clear cell endometrial carcinomas (UCCC) in the uccc_nih_2017 cohort revealed molecular heterogeneity: 27% serous-like (TP53/PPP2R1A), 20.6% endometrioid-like, 19.1% mixed, and 33.3% with no detectable alteration across the 7-gene + MSI panel; MSI was present in 11.3%; the molecular four-subgroup TCGA UCEC framework (POLE-ultramutated, MSI-hypermutated, copy-number-low, copy-number-high) provides context for CCEC classification. PMID:28485815
  • MC3 pan-cancer mutation-calling project (10,510 TCGA pairs) included UCEC; concordance with the legacy PanCan12 MAF exceeded 90% PMID:29596782
  • Pan-cancer fusion study (9,624 TCGA samples) included UCEC; ESR1 fusions were among the recurrent events spanning gynecological cancers; druggable fusions annotated across 29 cancer types including UCEC PMID:29617662
  • Pan-cancer aneuploidy study included UCEC in the gynecological arm-level cluster (alongside UCS); UCEC is an exception to the positive aneuploidy–mutation-rate correlation due to MSI-high and POLE-mutant cases; copy-number-high serous-like endometrial is a notable exception that clusters outside the typical UCEC pattern PMID:29622463

Subtypes

  • CN-H/TP53abn: 69% of Black vs. 35% of White ECs (P<0.001); associated with serous/carcinosarcoma histology, higher chromosomal instability (FGA 30% vs. 10%), and lower actionable alteration frequency. PMID:37651310
  • POLE-mutant: 1.2% Black vs. 5.8% White; favorable prognosis. PMID:37651310
  • MSI-H/dMMR: 14% Black vs. 25% White; eligible for immune checkpoint therapy. PMID:37651310
  • Serous carcinoma (USC): 29% Black vs. 13% White (P<0.01). PMID:37651310
  • Carcinosarcoma (UCS): 20% Black vs. 11% White (P<0.01). PMID:37651310

Therapeutic landscape

  • Nivolumab in dMMR/MSI-H UCEC: ORR 58.8% (7 CRs, 13 PRs), PFS24 64.7%, median PFS 21.6 months; TMB and PD-L1 were not predictive within dMMR-selected population. PMID:38653864
  • T cell functional states (dysfunctional CD8+PD-1+, terminally dysfunctional CD8+PD-1+TOX+) and spatial proximity to PD-L1+ cells predict nivolumab benefit (AUC=0.897, P=0.0007). PMID:38653864
  • ERBB2 amplification in Black patients represents a therapeutic opportunity with trastuzumab and T-DXd (including low-HER2-expressing carcinosarcomas). PMID:37651310
  • CCNE1 amplification (enriched in Black patients) is a potential target for WEE1 inhibitors, ATR inhibitors, and PKMYT1 kinase inhibitors. PMID:37651310
  • Only 22.4% of Black patients had OncoKB Level 1/2/3A actionable alterations vs. 39.7% of White patients (P<0.001), underscoring need for more diverse clinical trials. PMID:37651310

Sources

  • PMID:37651310 — Molecular characterization of endometrial carcinomas in Black and White patients reveals disparate drivers with therapeutic implications (Cancer Discovery, 2023)

  • PMID:38653864 — Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses (Nature Medicine, 2024)

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

  • PMID:28445112 — Reinikka et al. 2025; endometrial polyp WGS/RNA-seq; low-VAF UCEC-driver hotspot mutations in 26% KRAS, PIK3CA, PIK3R1, PTEN, ERBB2, FBXW7.

  • PMID:28481359

  • PMID:28485815

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