The Heidelberg histologic classification of renal cell tumors subdivides renal cell tumors into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most common documented genetic abnormalities (Kovacs et al., 1997). Malignant tumors are ... The Heidelberg histologic classification of renal cell tumors subdivides renal cell tumors into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most common documented genetic abnormalities (Kovacs et al., 1997). Malignant tumors are subclassified into common or conventional renal cell carcinoma (clear cell); papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and unclassified renal cell carcinoma. The common or conventional type accounts for about 75% of renal cell neoplasms and is characterized genetically by a highly specific deletion of chromosome 3p. Papillary renal cell carcinoma (see 605074) accounts for about 10% of renal cell tumors. Chromophobe renal cell carcinoma accounts for approximately 5% of renal cell neoplasms. Genetically, chromophobe RCC is characterized by a combination of loss of heterozygosity of chromosomes 1, 2, 6, 10, 13, 17, and 21 and hypodiploid DNA content. Collecting duct carcinoma accounts for about 1% of renal cell carcinoma. Renal cell carcinoma occurs nearly twice as often in men as in women; incidence in the United States is equivalent among whites and blacks. Cigarette smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one-third of cases. Obesity is also a risk factor, particularly in women. Other risk factors include hypertension, unopposed estrogen therapy, and occupational exposure to petroleum products, heavy metals, or asbestos (summary by Motzer et al., 1996). - Genetic Heterogeneity of Renal Cell Carcinoma Germline mutation resulting in nonpapillary renal cell carcinoma of the clear cell and chromophobe type occurs in the HNF1A gene (142410) and the HNF1B gene (189907). Somatic mutations in renal cell carcinomas occur in the VHL gene (608537), the TRC8 gene (603046), the OGG1 gene (601982), the ARMET gene (601916), the FLCN gene (607273), and the BAP1 gene (603089). See also RCCX1 (300854) for a discussion of renal cell carcinoma associated with translocations of chromosome Xp11.2 involving the TFE3 gene (314310). For a discussion of papillary renal cell carcinoma, see RCCP1 (605074). - Occurrence of Renal Cell Carcinoma in Other Disorders Von Hippel-Lindau syndrome (193300) is a familial multicancer syndrome in which there is a susceptibility to a variety of neoplasms, including renal cell carcinoma of clear cell histology and renal cysts. A syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma has been reported (605839). Medullary carcinoma of the kidney is believed to arise from the collecting ducts of the renal medulla and is associated with sickle cell trait (603903) (Kovacs et al., 1997). Renal cell carcinoma occurs in patients with the Birt-Hogg-Dube syndrome (135150). Bertolotto et al. (2011) identified a missense mutation in the MITF (156845) gene that increases the risk of renal cell carcinoma with or without malignant melanoma (CCMM8; 614456).
Familial renal cell carcinoma (RCC) is relatively rare. Reports (e.g., Franksson et al., 1972; Goldman et al., 1979) suggest an early average age at diagnosis and frequent bilateral or multiple primary tumors in familial cases. Rusche (1953) observed ... Familial renal cell carcinoma (RCC) is relatively rare. Reports (e.g., Franksson et al., 1972; Goldman et al., 1979) suggest an early average age at diagnosis and frequent bilateral or multiple primary tumors in familial cases. Rusche (1953) observed hypernephroma in 2 brothers. Both had distant metastasis as the first manifestation and both were in their early thirties at the time of diagnosis. Brinton (1960) described a family in which 2 brothers and a sister had hypernephroma. The father had died of kidney tumor and the mother of cancer, site unstated. One of the patients had polycythemia, a known accompaniment of hypernephroma on occasion. It should be noted that hypernephroma and cerebellar hemangioblastoma, which histologically resembles hypernephroma, are features of von Hippel-Lindau disease. Polycythemia also occurs with cerebellar hemangioblastoma. Jakesz and Wuketich (1978) reported an instructive family in which 3 brothers had bilateral renal cell carcinoma. The index case also had cerebellar hemangioblastoma. The authors suggested that von Hippel-Lindau disease was the fundamental problem. Braun et al. (1975) studied 3 families, each with multiple cases of renal cell carcinoma. There appeared to be an association with HLA W17 tissue type. Li et al. (1982) reviewed 9 families in which 2 or more members had renal carcinoma. Multiple generations were affected in 5, sibs in 4. The median age at diagnosis was a decade earlier than usual, and individual patients had bilateral or multifocal lesions; these are features of hereditary forms of diverse cancers. No patient had von Hippel-Lindau disease and none had 3;8 translocation. Levinson et al. (1990) reported that, since 1961, 28 families with multiple cases of renal cell carcinoma had been reported, with an abnormality in the constitutional karyotype having been found in only 1 family. They identified 5 more families in which a total of 12 relatives had renal cell carcinoma; peripheral blood karyotypes from 7 patients and 5 unaffected relatives showed no significant abnormalities. They suggested that members of families with multiple cases of renal cell carcinoma be screened with renal ultrasound initially at age 30, with repeat examinations every 2 or 3 years. The recommendations are similar to those for von Hippel-Lindau disease. Woodward et al. (2000) reported a clinical and molecular study of familial renal cell carcinoma in 9 kindreds with 2 or more cases of renal cell carcinoma in first-degree relatives. Familial RCC was characterized by an earlier age at onset (mean 47.1 years, 52% of cases less than 50 years of age) as compared to sporadic cases. Mutation analysis of the VHL (608537), MET (164860), and CUL2 (603135) genes revealed no germline mutations. Woodward et al. (2000) concluded that the VHL, MET, and CUL2 genes do not have a major role in familial renal cell carcinoma.
Although deletions on chromosome 3 had been suggested to be specific for the clear cell type, Anglard et al. (1992) could find no correlation between LOH and clear or granular cell types.
To explore the role ... Although deletions on chromosome 3 had been suggested to be specific for the clear cell type, Anglard et al. (1992) could find no correlation between LOH and clear or granular cell types. To explore the role of allelic losses at chromosome 3p25 and genetic alterations of chromosome 8, Yamaguchi et al. (2003) investigated the relationships between genetic alterations in these chromosomal regions and clinicopathologic findings (such as tumor size and grade), by employing FISH. They examined 50 Japanese clear-cell renal cell carcinomas with DNA probes for 3p25.3-p25.1 and probes for various locations on chromosome 8, specifically using a probe for MYC (190080), located at 8q24. Deletion at the 3p region was detected in 38 patients (76%); MYC gain was detected in 20 patients (40%). The deletion at 3p with MYC gain showed a significant correlation with tumor size.
Shimizu et al. (1990) introduced a single chromosome containing the short arm of chromosome 3 into a human renal cell carcinoma cell line via microcell fusion. They observed suppression of tumorigenicity in nude mice or modulation of tumor-growth ... Shimizu et al. (1990) introduced a single chromosome containing the short arm of chromosome 3 into a human renal cell carcinoma cell line via microcell fusion. They observed suppression of tumorigenicity in nude mice or modulation of tumor-growth rate in vitro. Gnarra et al. (1994) demonstrated that the VHL gene on chromosome 3p26-p25 was mutated in the tumors of individuals with familial renal carcinoma reported by Cohen et al. (1979); furthermore, a renal tumor from one of the affected individuals carrying the constitutional translocation t(3;8)(p14;q24) had loss of the VHL gene on the other chromosome. Thus the findings adhere to the Knudson 2-hit hypothesis as for many other tumors related to tumor suppressor genes. As outlined earlier, the 3;8 chromosomal translocation in the family reported by Cohen et al. (1979) suggested the existence of a locus on 3p underlying clear cell renal carcinoma. The frequent 3p loss of heterozygosity in sporadic RCC further led to the assumption that a critical tumor suppressor gene would be located at 3p14. Identification of the VHL gene at 3p25 provided an alternative explanation for at least some observed 3p loss of heterozygosity. Furthermore, van den Berg and Buys (1997) reported that region 3p21 may be involved in the malignant progression of renal tumors. Within 3p14, Ohta et al. (1996) identified the FHIT gene, which was interrupted in its 5-prime untranslated region by the 3;8 translocation. However, a number of findings suggested that FHIT was an unlikely causative gene in the hereditary t(3;8) family. The fact that FHIT in a case of parathyroid adenoma underwent fusion with the high mobility group protein gene HMGIC (600698), the causative gene in a variety of benign tumors (Geurts et al., 1997) suggested to Gemmill et al. (1998) that FHIT might be a bystander in the fusion with an alternative candidate gene on chromosome 8. By use of 5-prime rapid amplification of cDNA ends (RACE), Gemmill et al. (1998) identified a gene, which they called TRC8 (603046), with characteristics compatible with oncogenic properties. In addition, they identified a TRC8 mutation in a sporadic renal carcinoma. Rebouissou et al. (2005) screened 35 renal neoplasms for HNF1A (142410) and HNF1B (189907) inactivation. Biallelic HNF1B inactivation was detected in 2 of 12 chromophobe renal carcinomas, resulting from a germline mutation (189907.0014 and 189907.0015) and a somatic gene deletion. In these cases, the expression of PKHD1 (606702) and uromodulin (UMOD; 191845), 2 genes regulated by HNF1B, was turned off. In 2 of 13 clear cell renal carcinomas, the authors found monoallelic germline mutations (142410.0001 and 142410.0022) of HNF1A with no associated suppression of target mRNA expression. In normal and tumor renal tissues, there was a network of transcription factors differentially regulated in tumor subtypes. There were 2 related clusters of coregulated genes associating HNF1B, PKHD1, and UMOD in the first group and HNF1A, HNF4A (600281), FABP1 (134650), and UGT2B7 (600068) in the second group. Rebouissou et al. (2005) suggested that germline mutations of HNF1B and HNF1A may predispose to renal tumors. Furthermore, they proposed that HNF1B may function as a tumor suppressor gene in chromophobe renal cell carcinogenesis through control of PKHD1 expression. To determine further the genetics of clear cell renal cell carcinoma, Dalgliesh et al. (2010) sequenced 101 cases through 3,544 protein-coding genes and identified inactivating mutations in 2 genes encoding enzymes involved in histone modification: SETD2 (612778), a histone H3 lysine-36 methyltransferase; and JARID1C (314690), a histone H3 lysine-4 demethylase. They also found mutations in the histone H3 lysine-27 demethylase UTX (300128), in which mutations had been reported previously in other tumor types. Dalgliesh et al. (2010) concluded that their results highlighted the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 (607379) mutations were found in non-VHL mutated clear cell renal cell carcinoma, and several other probable cancer genes were identified. Varela et al. (2011) sequenced the protein coding exome in a series of primary clear cell renal cell carcinoma (ccRCC) and reported the identification of mutations in PBRM1 (606083) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. Varela et al. (2011) concluded that their data further elucidated the somatic genetic architecture of ccRCC and emphasized the marked contribution of aberrant chromatin biology. Pena-Llopis et al. (2012) provided evidence that the BAP1 gene (603089) can act as a tumor suppressor gene in clear cell renal cell carcinoma. The authors used whole-genome and exome sequencing of ccRCC tumors as well as analyses of mutant allele ratios of a murine tumorgraft to identify putative 2-hit tumor suppressor genes. BAP1 was found to be somatically mutated in 24 (14%) of 176 tumors, and most mutations were predicted to truncate the protein. In a cell line with a missense BAP1 mutation, expression of wildtype BAP1 repressed cell proliferation without causing apoptosis. In this cell line, the majority of BAP1 cofractionated with and bound to HCFC1. Mutations disrupting the HCFC1 binding motif impaired BAP1-mediated suppression of cell proliferation, but not its deubiquitination of monoubiquitinated histone 2A. BAP1 loss sensitized RCC cells in vitro to genotoxic stress. Although mutations in BAP1 and PBRM1 anticorrelated in renal cell tumors, the few tumors that had combined loss of BAP1 and PBRM1 were associated with rhabdoid features. Moreover, BAP1 loss was associated with high tumor grade. - Reviews Motzer et al. (1996) reviewed all aspects of renal cell carcinoma in detail, including the molecular genetic abnormalities and the evidence for a locus on 3p distinct from the von Hippel-Lindau gene; the VHL gene is involved in the great majority of cases of renal cell carcinomas of the clear cell type. Bodmer et al. (2002) reviewed the molecular genetics of familial and nonfamilial cases of RCC, including the roles of VHL, MET, and translocations involving chromosomes 1, 3, and X.