Abstract P50: Whole Genome Sequencing Reveals a High Incidence of Germline Pathogenic Variants in Genes Associated with Sarcoma Across Subtypes

Abstract Sarcomas are heterogeneous mesenchymal cancers originating from bone and soft tissue, accounting for 1% of adult and 21% of paediatric solid tumours 1. Despite their sporadic nature, sarcomas have been linked to genetic predisposition, particularly in children, contributing to their poor prognosis and subtype-specific genomic alterations 23. This study aims to identify pathogenic variants predisposing individuals to sarcoma, thereby enhancing genetic screening, prognosis, and treatment. Additionally, it seeks to investigate genotype-phenotype correlations and explore genetic differences across subtypes. We included 115 probands from the National Cancer Centre Singapore, comprising 50% liposarcomas, 45% leiomyosarcomas, and 5% malignant peripheral nerve sheath tumours (MPNST). The median age of diagnosis was 54 years with a balanced gender ratio. Whole genome sequencing on peripheral blood DNA was performed using Illumina short reads, and germline variants were called with both DeepVariant and GATK HaplotypeCaller. Pathogenic (P) and likely pathogenic (LP) variants were identified following ACMG criteria. Our analysis revealed 5. 2% of probands carried at least one P variant, while 10. 4% carried at least one LP variant in genes associated with sarcoma risk, such as DMNT3A, NF1, TP53, and TYK2. One notable case involves a proband with both NF1 and TYK2 variants, where our analysis suggests that both variants likely contribute to the development of liposarcoma, as NF1 loss-of-function variants and TYK2 mutations have been implicated in sarcoma and related cancer syndromes 45. To ensure the accuracy of our findings, all identified P and LP variants will be validated through Sanger sequencing, strengthening the evidence for their role in sarcoma predisposition. In conclusion, our study highlights the need for genetic screening in patients with sporadic sarcomas. Citation Format: Isaac Lin, Rutharra Ghayadthri Manisekaran, Joanne Ngeow. Whole Genome Sequencing Reveals a High Incidence of Germline Pathogenic Variants in Genes Associated with Sarcoma Across Subtypes abstract. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P50.