Uterine Carcinosarcoma (UCS)

Overview

Uterine carcinosarcoma (UCS), also known as malignant mixed Mullerian tumor (MMMT), is an aggressive biphasic uterine malignancy with both carcinomatous and sarcomatous components. On OncoTree it is a child of endometrial carcinoma (UCEC). It carries a worse prognosis than uterine endometrioid carcinoma and is more common in older patients. It is enriched in the CN-H/TP53abn molecular subgroup.

Cohorts in the corpus

  • Part of the 1,882-patient endometrial carcinoma cohort (259 Black, 1,623 White patients) at MSK, profiled by MSK-IMPACT. UCS constituted 20% of ECs in Black patients vs. 11% in White patients. Dataset: ucec_ancestry_cds_msk_2023. PMID:37651310

Recurrent alterations

  • TP53 — mutations highly prevalent in UCS, consistent with CN-H/TP53abn subtype enrichment. PMID:37651310
  • CCNE1 — amplification enriched in carcinosarcomas from Black patients (29% vs. 10% White, q<0.1). PMID:37651310
  • KMT2B — mutations enriched in carcinosarcomas from Black patients (31% vs. 10% White, q<0.1). PMID:37651310
  • NF1 — mutations more frequent in carcinosarcomas from Black patients (12% vs. 1% White, q<0.1). PMID:37651310
  • Whole-exome sequencing of 17 uterine carcinosarcomas (plus 5 ovarian) found TP53 (67%), PIK3CA (41%), PTEN (41%), KRAS (27%), and chromatin-remodelling genes in ~64% of cases (ARID1A 32%, KMT2C 27%, BAZ1A 18%); >75% of cases harboured potentially actionable alterations PMID:25233892
  • Pan-cancer fusion study (9,624 TCGA samples) included UCS as one of 33 TCGA cancer types; druggable fusions annotated across 29 cancer types including UCS PMID:29617662
  • Pan-cancer aneuploidy study found UCS has one of the highest aneuploidy scores (96% of samples with any event, mean score 17.2); UCS clustered in the gynecological arm-level group alongside UCEC; UCS is an exception to the positive aneuploidy–mutation-rate correlation due to MSI/POLE cases PMID:29622463

Subtypes

  • Carcinosarcoma is more common in Black patients (20% vs. 11%, P<0.01). PMID:37651310
  • Black patients with UCS show different genomic drivers (CCNE1 amplification, KMT2B and NF1 mutations) compared to White patients. PMID:37651310

Therapeutic landscape

  • ERBB2 amplification in Black patients with UCS represents a therapeutic opportunity; trastuzumab deruxtecan has shown clinical activity even in low-HER2-expressing carcinosarcomas. PMID:37651310
  • CCNE1 amplification (enriched in Black patients with UCS) is a potential target for WEE1 inhibitors and ATR inhibitor combinations. PMID:37651310

Sources

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

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