Fusion gene heterogeneity and kinase enrichment in high-grade serous carcinomas.

Genomic instability in high-grade serous tubo-ovarian carcinoma (HGSTOC) can generate fusion genes with potential roles in tumor evolution and clinical relevance. HGSTOCs commonly disseminate prior to diagnosis, but most studies analyze only one tumor sample per patient, limiting understanding of fusion gene dynamics. Here, RNA sequencing was performed on 108 tumor samples from multiple intra‑abdominal sites in 23 patients. A consensus approach involving three fusion callers identified 170 high-confidence fusion genes present in all samples from each patient, most of which were non‑recurrent and not in-frame. Protein kinases were significantly enriched among fusion partners, and commonly retained intact catalytic domains. Several of the kinase fusion genes may have oncogenic relevance, including AKAP8L::BRD4 (recurrent in three patients), GPBP1L1::MKNK1, SPAG16::ERBB4, UGP2::MAPK4, and STRN3::PRKD1. Four fusions involved homologous recombination-related genes, including FUT10::SPIDR, RAD54B::VIRMA, RAD54L::PLXNA2, and SMARCAD1::BOD1L1. Integration of these fusion genes with other somatic alterations in homologous recombination-related genes, deficiency signatures, and germline BRCA1/2 variants increased the involvement of the homologous recombination pathway to 15 HGSTOCs (65%). Overall, HGSTOC has a heterogeneous fusion gene landscape, and multi-site sampling with consensus calling offers a robust strategy for resolving fusion profiles.