Clinical Information

Lifetime risk for developing renal cancer in the United States is approximately 1% to 2%.(1) Of these cases, about 3% to 5% are associated with an underlying hereditary predisposition.(2,3) Suspicion for a hereditary association may be raised in cases of early age of onset, multifocal/bilateral lesions, or a family or personal history of renal or other tumors.

Clear cell type renal cancers can be seen in individuals with disease-causing variants in BAP1, PTEN, and VHL. BAP1 variants also associated with an increased risk for melanomas, mesothelioma, and epithelioid atypical Spitz tumors. PTEN variants are also associated with significantly increased risk for breast, thyroid, and uterine cancer. VHL variants are associated with von Hippel Lindau syndrome and are associated with an increased risk for several types of tumors, including hemangioblastomas, pancreatic cysts, neuroendocrine tumors, endolymphatic sac, and epididymal tumors.(4)

Risk for renal cancer is also increased by disease-causing variants in the succinate dehydrogenase-associated genes: SDHAF2, SDHA, SDHB, SDHC and SDHD.(5-8)

Variants in the SDH genes are also associated with an increased risk for paragangliomas and pheochromocytomas.

Hereditary papillary renal cancer may be caused by variants in the MET gene, while alterations in the FH gene cause a syndrome called hereditary leiomyomatosis and renal cell cancer (HLRCC). Individuals with HLRCC also have an increased risk of developing cutaneous or uterine leiomyomas.(2)

Birt-Hogg-Dube syndrome is caused by disease-causing variants in the FLCN gene. Individuals with Birt-Hogg-Dube syndrome have an increased risk for oncocytic or chromophobe renal cancers and often exhibit other features such as fibrofolliculomas, lung cysts, and pneumothorax.

Angiomyolipomas and morphologically heterogenous renal tumors may be seen in individuals with tuberous sclerosis complex (TS), caused by variants in the TSC1 or TSC2 genes.(9) Individuals with TS are also at increased risk for subependymal giant cell astrocytomas and may exhibit several other features, including facial angiofibromas, lymphangioleiomyomatosis, cardiac rhabdomyomas, hypomelanocytic macules, shagreen patches, and ungual/periungual fibromas.(10)

Disease-causing DICER1 variants are associated with an increased risk of developing kidney tumors called cystic nephromas, although some individuals with DICER1 variants have developed high-grade renal sarcomas.(11) DICER1 tumor predisposition syndrome is also characterized by risk for pleuropulmonary blastoma, pulmonary cysts, thyroid tumors, and ovarian tumors, in addition to other features.(12)

A specific variant within the MITF gene, p.E318K, is associated with increased risk for melanoma as well as renal cancer.(13)

Lastly, disease-causing variants within the SMARCA4 and SMARCB1 genes cause a hereditary cancer syndrome called rhabdoid tumor predisposition syndrome, characterized by a significantly increased risk for aggressive, childhood-onset rhabdoid tumors, including rhabdoid tumors of the kidney.(14)

The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with hereditary renal cancer syndromes.(15)