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Molecular biomarkers in uterine sarcomas: a review of reviews with genomic data integration
V Iacobelli1, V Romano2, G Anderson1
1Unit of Oncological Gynecology, Women's Children's and Public Health Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.
Background:
Uterine sarcomas (US) account for 3-7% of uterine malignancies but cause disproportionate high cancer-related mortality. Despite expanding molecular profiling, evidence remains fragmented across histological categories, limiting translation into validated prognostic tools and actionable therapeutic targets.
Methods:
We conducted a comprehensive review, searching MEDLINE, Scopus, Web of Science, and ProQuest. Eligible studies were systematic or high-quality narrative reviews evaluating molecular biomarkers with diagnostic, prognostic, or predictive relevance in US. Methodological quality was assessed using AMSTAR-2 and SANRA, and pooled prevalence estimates derived using random-effects models, complemented by publicly available genomic dataset analysis.
Results:
Twenty-nine reviews met inclusion criteria, encompassing leiomyosarcoma (LMS), endometrial stromal sarcoma (ESS), adenosarcoma, perivascular epithelioid cell tumor (PEComa), and uterine tumor resembling ovarian sex cord tumor; after de-duplication, they contributed 71 distinct primary studies comprising 1812 unique patients. Thirty-seven molecular biomarkers with potential clinical relevance were identified. In ESS, grade-stratified analysis separated the two entities sharply: hormone receptor estrogen (ER) and progesteron (PR) were expressed in 82% and 92% of low-grade ESS (LG-ESS) versus 38% and 47% of high-grade ESS (HG-ESS) (between-stratum p < 0.001 and p = 0.002) defining a hormone-responsive, therapeutically actionable profile in LG disease. HG-ESS was characterized by Cyclin D1 overexpression (68%) and by YWHAE-NUTM2A/B (42%) and ZC3H7B-BCOR rearrangements (36%) rearrangements. LMS was characterized by TP53 (68%) and RB1 (48%) co-inactivation. PEComa demonstrated mTOR pathway activation (MelanA 79%), consistent with established mTOR inhibitor sensitivity. High clinical actionability (ESCAT tiers I-II) was confined to rare kinase fusions, while most biomarkers remained at lower evidence levels.
Conclusions:
Molecular profiling is essential for histotype classification in US and increasingly informative for prognostic stratification, yet predictive utility remains largely confined to a subset of tumor types. Prospective biomarker-driven trials are needed to bridge the persistent gap between biological discovery and clinical implementation.