Individuals with germline activating c-Met
mutations are highly predisposed to Type 1 papillary renal carcinoma, often associated with duplication of the mutant c-Met
allele located at 7q31 16,17
(see Table 39-1
encodes a receptor tyrosine kinase that influences cellular proliferation, survival, invasion, and metastasis. Somatic c-Met
mutations are relatively rare in sporadic papillary renal carcinomas (see Table 39-3
Germline loss-of-function fumarate hydratase (1q42) mutations cause a syndrome characterized by Type 2 papillary renal carcinoma, cutaneous leiomyomata, and uterine fibroids, whereas succinate dehydrogenase subunit mutations cause familial paragangliomas and, rarely, clear cell renal carcinomas (see Table 39-1
). Inactivation of fumarate hydratase and succinate dehydrogenase leads to the intracellular accumulation of fumarate and succinate, respectively, which competitively inhibit 2-oxoglutarate-dependent enzymes including the EglN prolyl hydroxylases (see Figure 39-1
). Accordingly, HIFα levels are increased in FH–/–
tumors. It has also been shown that the secondary accumulation of succinate in fumarate hydratase–deficient cells can also, through covalent linkage to a cysteine residue, inactivate the KEAP tumor suppressor protein, leading to deregulation of the NRF2 transcription factor.
Inactivating germline mutations of FLCN
(17p11.2) cause Birt-Hogg-Dube syndrome, which is characterized by a variety of dermatological lesions, including fibrofolliculomas; renal tumors including oncocytomas and chromophobe tumors and, less commonly, papillary and clear cell carcinomas; and pulmonary cysts (see Table 39-1
). The FLCN
gene product, Folliculin, binds to FNIP1 and FNIP2 and is believed to modulate nutrient sensing by the mTOR signaling pathway. Folliculin also appears to suppress TGFβ as well as the expression of TFE3, the common partner in kidney cancers linked to Xp11.2 translocations. Inactivating mutations of either TSC1
(9q34), which encodes hamartin, or TSC2
(16p13), which encodes tuberin, cause tuberous sclerosis. Tuberous sclerosis is associated with cutaneous, neurological, and renal abnormalities. Renal abnormalities include angiomyolipomata and, less commonly, clear cell renal carcinoma (see Table 39-1
). Hamartin and tuberin form a complex that inhibits the mTOR kinase and regulates VEGF via both mTOR-dependent and independent pathways (Figure 39-2
). Somatic TSC1
mutations have been described in sporadic ccRCC, as have mutations in other genes whose products link growth factor signaling, via hamartin and tuberin, to mTOR activity (see later discussion). Inactivation of the hamartin/tuberin complex in mice causes renal cysts, and a germline TSC2
mutation in the rat (Eker Rat) causes clear cell carcinoma.
Figure 39-2 Kidney cancer mutations with an impact on mTOR Proteins that have been targets of mutations in kidney cancer are indicated by asterisks.
Some families predisposed to clear cell carcinoma carry germline translocations involving chromosome 3 and variable partners (see Table 39-1
). Loss of the derivative chromosome 3p segment is believed to cause loss of tumor suppressors, such as VHL
, located between 3p21 and 3p25.
Figure 39-3 Multistep kidney carcinogenesis (A) Multiple renal cancer suppressors are located on chromosome 3p, including VHL at 3p25 and SETD2, BAP1, and PBRM1 on 3p21. For this reason three genetic “hits” can inactivate two tumor suppressors (and four “hits,” three tumor suppressors) provided one of the hits is chromosome 3p loss. In the example shown both VHL and PBRM1 have been inactivated. (B) pVHL loss leads to preneoplastic renal lesions, such as VHL–/– renal cysts. In VHL disease the kidney is germline VHL+/–, whereas in sporadic kidney cancers the kidney is germline VHL+/+. Additional genetic changes, such as PBRM1 or BAP1 mutations, loss of chromosome 14q, and gain of chromosome 5q, are linked to progression to clear cell renal carcinoma.