Hereditary Cancer and Genetics in Renal Cell Carcinoma

Approximately 5-8% of kidney cancers are associated with hereditary renal cell carcinoma (RCC) syndromes. Over the past two decades, our knowledge of the causative genes and altered metabolic pathways implicated in the development of RCC has significantly expanded. There are at least nine autosomal dominant hereditary syndromes associated with increased inherited risk of RCC related to germline mutations in VHL, MET, FH, TSC1/2, FLCN, SDHA/B/C/D, BAP1, and MITF. While some syndromes, such as von Hippel-Lindau, are well defined, the clinical spectrum of syndromes associated with SDH, BAP1, and MITF is still being characterized. Knowledge of the genetic basis of kidney cancer can guide management of at-risk patients, including active surveillance and preservation of renal function in patients with more indolent RCC, such as those associated with VHL and MET mutations, and more aggressive surgical management in patients with localized FH-deficient RCC. Targeted therapeutic options for advanced kidney cancers associated with hereditary RCC syndromes are an area of active clinical research. Here we summarize the causative genes, dysregulated pathways, clinical characteristics, and recommended managements for patients with hereditary RCC syndromes.