TITLE: “Evolutionary Consequences of Tumor Initiation in Hereditary Leiomyomatosis and Renal Cell Cancer”
ABSTRACT: Hereditary leiomyomatosis and renal cell cancer (HLRCC ) is a rare hereditary condition with individuals at risk of developing renal cell carcinoma (RCC) associated with poor prognosis. Although RCC risk and cancer penetrance of this condition has been studied, whole genome sequencing of associated tumors has yet to be examined, and the landscape of structural variants of HLRCC is largely unknown. We have therefore performed whole genome sequencing of tumor/normal pairs of HLRCC patients to study the tumor molecular architecture in this form of RCC. Through germline variant and somatic mutation calling, we have identified specific somatic mutational drivers, including those at the structural variant level for the first time in HLRCC. Similarly, using tumor subclonal reconstruction techniques, we have inferred the clonality of HLRCC-associated RCC tumors and elucidate the relative timing of key oncogenic events and mutational processes. These studies shed key light on the specific mutational processes and drivers of this rare hereditary malignancy and on its lethality.
