Abstract 2280: Whole-exome sequencing analysis of early-onset soft tissue sarcoma in a multiethnic family-based population study

Abstract Background: Sarcomas are a rare group of cancers originating in bones and soft tissues, and represent approximately 1% of adult cancers and 15-20% of pediatric cancers. The development of sarcomas is often driven by inherited or de novo mutations in genes involved in critical processes such as cell growth, development, and signaling pathways, which play central roles in their pathogenesis. Notably, the risk of early-onset cancer (diagnosed before the age of 29) is significantly elevated—68 times higher—in siblings of individuals with soft tissue sarcomas, suggesting a strong contribution of inherited germline variants to the observed familial cancer risk. Methods: Cancer patients included in this study were identified using a linked dataset integrating information from the California Cancer Registry and the California Birth Statistical Master File. To explore rare genetic predispositions associated with soft tissue sarcomas, a cohort of 54 patients from 43 families was analyzed. This cohort included 11 sibling pairs, each with at least one individual diagnosed with soft tissue sarcoma, ICDO-3 histology code 8900-8991. Additionally, 32 unrelated individuals diagnosed with multiple cancers, including soft tissue sarcoma, were included in the analysis. Whole-exome sequencing (WES) was performed on neonatal dried blood samples from these 54 participants. Germline short variant discovery, including single nucleotide variants and insertions/deletions (indels), was conducted using the Genome Analysis Toolkit pipeline. Variants were annotated according to guidelines from the American College of Medical Genetics and Genomics. Results: A total of 603 cancer-associated variants were identified in this study, with 74 variants detected in multiple individuals. Among these, 12 variants were classified as “Pathogenic/Likely Pathogenic, ” two of which were found in two children each. Notably, a mutation in the NF1 gene, previously linked to Neurofibromatosis Type 1 syndrome, was confirmed in a Latino-White family, where one child presented with mixed-type rhabdomyosarcoma and another with neurofibroma. Additionally, a novel association was observed between the USP6 gene mutation and rhabdomyosarcoma diagnosis in two unrelated Southeast Asian individuals, one of Filipino descent and the other Guamanian. Furthermore, a homozygous mutation in the AR gene on the X chromosome was identified in a single patient. Conclusion: Our study employs WES analysis to investigate predisposition genes in individuals diagnosed with soft tissue sarcoma, alongside their cancer-affected siblings. Through this analysis, we have identified novel genetic mutations linked to soft tissue sarcoma diagnosis. Additionally, certain variants appear to exhibit ancestry-specific patterns in this multiethnic population. Citation Format: Naying Zhou, Joseph L. Wiemels. Whole-exome sequencing analysis of early-onset soft tissue sarcoma in a multiethnic family-based population study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2280.