Abstract
Abstract Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify novel pathways specific to mesenchymal cancers, whole genome germline sequencing was performed on 1,644 sporadic cases, and 3,205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare variant burden and ontologic analysis identified two new sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, while heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas. Citation Format: David M. Thomas. A population-based, whole genome sequencing approach to mapping the genetic basis of mesenchymal malignancies [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA030.
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