Uterine Serous Carcinoma (USC)

Overview

Uterine serous carcinoma (USC), also known as uterine papillary serous carcinoma (UPSC), is an aggressive high-grade endometrial malignancy analogous to high-grade serous ovarian carcinoma. On OncoTree it is a child of endometrial carcinoma (UCEC). It is predominantly TP53-mutant (CN-H/TP53abn molecular subtype) and carries a worse prognosis than low-grade endometrioid carcinoma.

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. USC constituted 29% of ECs in Black patients vs. 13% in White patients. Dataset: ucec_ancestry_cds_msk_2023. PMID:37651310

Recurrent alterations

  • TP53 — near-universal in USC, defining the CN-H/TP53abn molecular subtype. PMID:37651310
  • MED12 — hotspot mutations (p.G44A/D/S/R/V) more prevalent in serous ECs from Black patients (11% vs. 0% White). PMID:37651310
  • FBXW7 — co-occurs with TP53 mutations in serous/carcinosarcoma ECs. PMID:37651310
  • BRCA1 — somatic mutations more frequent in CN-H/TP53abn ECs from Black patients (3% vs. 0.3%). PMID:37651310
  • TCGA analysis of 53 uterine serous carcinomas revealed ERBB2 focal amplification with overexpression in 25%, TP53 mutation in ~91%, and molecular similarities to HGSOC and basal-like breast carcinoma (shared SCNA patterns, MC3 methylation profile); PIK3CA, FBXW7, PPP2R1A, and ARID1A mutations were >30% more frequent in USC than in HGSOC PMID:23636398
  • Cross-histology analysis of 63 uterine clear cell carcinomas (CCECs) against 45 uterine serous carcinomas (USC) and 40 endometrioid carcinomas (UEC) showed: 75.5% of USC had serous-like or mixed molecular profiles (TP53/PPP2R1A enrichment); TAF1 was previously nominated as a candidate driver in USC before its identification in CCEC in this study. PMID:28485815

Subtypes

  • USC is enriched in Black patients (29% vs. 13%, P<0.01). PMID:37651310
  • MED12 hotspot mutations distinguish serous ECs from Black patients; MED12 hotspot mutations were absent in serous ECs from White patients in this cohort. PMID:37651310

Therapeutic landscape

  • ERBB2 amplification (enriched in Black patients) represents a therapeutic target; trastuzumab and trastuzumab deruxtecan are under investigation for serous endometrial cancer. PMID:37651310
  • Lower frequency of MSI-H/dMMR in Black patients with serous histology reduces eligibility for immune checkpoint inhibitors in this subgroup. 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:23636398 — Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 2013.

  • PMID:28485815

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