Molecular differences between ovarian and uterine carcinosarcomas

Carcinosarcomas, also known as malignant mixed Müllerian tumors (MMMTs), are rare and aggressive neoplasms characterized by the coexistence of both carcinomatous (epithelial) and sarcomatous (mesenchymal) components. These tumors primarily arise in the uterus and less frequently in the ovary. Despite histological similarities, ovarian and uterine carcinosarcomas differ in epidemiology, clinical presentation, prognosis, and treatment strategies. Understanding the molecular differences between ovarian and uterine carcinosarcoma is essential for accurate diagnosis, effective treatment planning, and improved patient outcomes.In this study, whole-exome sequencing (WES) was performed on three ovarian and three uterine carcinosarcomas, along with matched normal blood or tissue DNA. Sequencing libraries were prepared using the Twist Library Preparation and Capture Kit and sequenced on NovaSeq X 25B with 150 bp paired end reads, generating an average of >900 million reads per sample.Somatic variants (missense and indels; n = 1,971-2,542) were identified across samples. Notably, a novel germline mutation in TBC1D32 (p.Thr375Lys) was detected in five of the six carcinosarcomas. TBC1D32 is primarily associated with genetic disorders such as ciliopathies and hypopituitarism, and although mutations have been reported in various cancers, its role as an oncogene or tumor suppressor remains unclear. While the overall number of variants did not differ significantly between ovarian and uterine carcinosarcomas, several somatic variants were unique to ovarian carcinosarcoma, including alterations in ANKDD1A and RPL10. ANKDD1A functions as a tumor suppressor; frequently silenced in glioblastoma via hypermethylation. RPL10 influences cancer through protein synthesis and extra-ribosomal functions; overexpression and mutations linked to tumor development. Validation of these variants in additional carcinosarcoma samples is ongoing. Furthermore, RNA sequencing using the Illumina Stranded Total RNA Prep Ligation with Ribo-Zero Plus Kit and NovaSeq X 25B (100 bp paired-end reads) is being conducted to identify differentially expressed genes between ovarian and uterine carcinosarcomas. Data analysis is currently in progress. In conclusion, we identified a recurrent germline mutation in TBC1D32 (p.Thr375Lys) across both ovarian and uterine carcinosarcomas, as well as somatic variants unique to ovarian carcinosarcoma. Further investigation of these genes may provide insights into carcinosarcoma pathogenesis and inform the development of differential treatment strategies for ovarian versus uterine disease.