Enhancing the detection of clinically relevant biomarkers in advanced uterine and tubo-ovarian carcinomas through genome-wide analysis.

Background: Advanced-stage tube-ovarian cancers (TOC) and uterine cancers (UC) significantly contribute to cancer mortality. While surgery achieves clinical remission in most cases, recurrence often necessitates systemic therapy. Recent molecular phenotype studies have advanced targeted therapies. We employed whole genome sequencing (WGS) to investigate biomarkers in gynecologic malignancies.

Design: Ninety-one tumor samples (45 TOC, 46 UC) were analyzed for germline mutations, somatic driver mutations, rearrangements, genome-wide signatures, and molecular phenotypes. A WGS-based high-confidence classifier for homologous recombination deficiency (HRD) was applied. Genomic profiles were correlated with clinical outcomes.

Results: The HRD phenotype was identified in serous carcinoma components, with 50 % of HRD cases showing BRCA1/2 wildtype (33 %) or variants of unknown significance (17 %). HRD correlated with better overall survival in tubo-ovarian serous carcinoma and was linked to responses to platinum therapy and PARP inhibitors. Endometrioid carcinomas showed no HRD phenotype despite BRCA1/2 variants. CDK12-type genomic instability (10 %) occurred in cases with CDK12 rearrangements, and CCNE1 gain (8 %) was observed in CCNE1-amplified cases, independent of copy number. In endometrioid carcinoma, mismatch repair (MMR) deficiency single base substitution signatures, particularly SBS44, contributed to high tumor mutation burden (TMB). Ultra-high TMB was found in two cases with pathogenic POLE and POLQ mutations, exhibiting multiple SBS signatures, including MMR deficiency.

Conclusion: Comprehensive genomic profiling of advanced-stage TOC and UC via WGS reveals key biomarkers and therapeutic targets, enhancing diagnostic accuracy and advancing personalized medicine in gynecological cancers.