Heritable defects in telomere and mitotic function selectively predispose to sarcomas

Abstract

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specificpathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived fromembryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Usingan extreme phenotype design, a combined rare-variant burden and ontologic analysis identified twosarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes arelinked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defectsin the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studiesindicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.