Renal Cell Carcinoma, Nonpapillary
A number sign (#) is used with this entry because mutations in several genes have been demonstrated to lead to renal cell carcinoma, either familial or sporadic.
DescriptionThe 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 (CMM8; 614456).
Clinical FeaturesFamilial 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.
CytogeneticsTranslocations and Deletions Involving Chromosome 3p
Cohen et al. (1979) described a family in which members with an inherited chromosomal translocation, t(3;8)(p21;q24), were predisposed to renal cancer. In 1 patient, cancer developed in residual renal tissue after partial nephrectomy. One patient had polycythemia. In the family reported by Cohen et al. (1979), Wang and Perkins (1984) used high resolution prometaphase G-banding analysis to demonstrate that the breakpoints occurred at the subbands 3p14.2 (not 3p21) and 8q24.1.
Because of the findings of the role of the MYC gene (190080), located at 8q24, in Burkitt lymphoma with reciprocal translocation between 8q24 and 14q32, the possibility exists that a similar mechanism is involved in the translocation between 8q24 and 3p21 in the family reported by Cohen et al. (1979). All 10 members of the family that developed renal cancer carried the translocation, whereas no member with a normal karyotype had renal cancer. Another oncogene, RAF1 (164760), has been assigned to chromosome 3 (3p25), but its possible role in RCC (or in small cell cancer of the lung, 182280, which also is related to chromosome 3p) is unknown. Harris et al. (1986) sorted the chromosome from a cell line established from a subject with the t(3;8)(p14.2;q24.1) translocation. They found that the RAF1 gene was translocated to the derivative chromosome 8 and, conversely, that the MYC gene was translocated to the derivative chromosome 3.
By in situ hybridization with an RAF1 probe, Teyssier et al. (1986) showed that in 2 renal cancers with 3p deletion, the oncogene had shifted from 3p25 to 3p14. By the use of cosmid cloning, Harris et al. (1986) showed that there was no rearrangement 31 kb 5-prime or 19 kb 3-prime to the translocated MYC gene. Gemmill et al. (1989) found that a 1.5-Mb segment surrounding MYC did not include the translocation breakpoint in familial RCC with t(3;8); thus, again, MYC seems not to be implicated in the development of RCC.
Li et al. (1993) followed up on the family reported by Cohen et al. (1979). Renal carcinoma had recurred in all 5 patients carrying the 3;8 translocation at 1 to 16 years after resection. Two translocation carriers with renal carcinoma also had thyroid cancer. Cancer was the cause of death in 3 patients; 2 were in a second remission. The tumors from 3 family members consistently showed loss of the entire derivative chromosome 8, which bore the segment 3pter-p14. In contrast, no genetic change was detected in the derivative chromosome 3 or in normal chromosomes 3 and 8. One interpretation from these findings is that the breakpoints in chromosomes 3 and 8 per se had no relevance to the renal carcinoma. Instead, the renal carcinoma was related to the tendency toward loss of the terminal part of 3p containing the von Hippel-Lindau gene (VHL) in the tumors of the affected patients.
Ohta et al. (1996) pointed out that a 200- to 300-kb region of 3p14.2, including the fragile site locus FRA3B, is homozygously deleted in multiple tumor-derived cell lines. By exon amplification from cosmids covering this deleted region, they identified the human gene called FHIT (601153) for 'fragile histidine triad gene.' The gene encodes a protein with 69% similarity to an enzyme of Schizosaccharomyces pombe, diadenosine 5-prime,5-triple prime-P(1),P(4)-tetraphosphate, asymmetric hydrolase. They found that the FHIT locus is composed of 10 exons distributed over at least 50 kb, with three 5-prime untranslated exons centromeric to the RCC-associated 3p14.2 breakpoint, the remaining exons telomeric to this translocation breakpoint, and exon 5 within the homozygously deleted fragile region. Aberrant transcripts of the FHIT locus were found in approximately 50% of esophageal, stomach, and colon carcinomas. The first 3 exons of the gene mapped centromeric to the t(3;8) break and between the break and the 5-prime end of the PTPRG gene (176886).
Pathak and Goodacre (1986) found reciprocal translocations involving 3p14-p13 and chromosomes 6, 8, 11 and 16. Yoshida et al. (1986) found rearrangement of chromosome 3 in 8 of 12 nonfamilial renal cell carcinomas. Using RFLPs, Zbar et al. (1987) examined tumors from 18 patients with nonhereditary renal cell carcinomas and found loss of alleles at loci on the short arm of chromosome 3 in all 11 of the patients who could be evaluated.
Szucs et al. (1987) described deletion of 3p as the only chromosome loss in a nonfamilial renal cell carcinoma. The deletion was thought to be at 3p11. The tumor also contained t(Y;3).
Carroll et al. (1987) found clonal abnormalities affecting the short arm of chromosome 3 in the 3p21-p12 region in 5 of 6 clear cell renal carcinomas. In the remaining case, of 15 karyotyped metaphases suitable for interpretation, 1 showed a deletion in 3p.
In tumor cells from a patient with renal cell carcinoma and von Hippel-Lindau disease, King et al. (1987) found a deletion in proximal 3p, thus providing support for the idea that genetic material in this area is critical to the development of RCC. In 22 of 25 primary renal cell carcinomas, Kovacs et al. (1987) found an aberration of chromosome 3, deletion of 3p, or translocation of chromosome segments to the deleted chromosome 3. The breakpoints in rearrangements of chromosome 3 clustered in the region of 3p13-p11.2. In 8 of the 25 RCCs, the rearrangement of chromosome 3 was the only karyotype change.
Kovacs and Hoene (1988) studied a patient with renal cancer and a constitutional reciprocal translocation t(3;12)(q13.2;q24.1). They found that tumor cells were characterized by loss of the derivative chromosome 3, supporting the hypothesis that loss of a specific 3p segment is associated with the development of renal cancer.
Kovacs et al. (1988) examined renal cell carcinoma and normal kidney tissues from 34 patients with sporadic, nonhereditary RCC. Of the 21 cytogenetically examined tumors, 18 had a detectable anomaly of 3p distal to band 3p11.2-p13, combined with the nonreciprocal translocation of a segment from another chromosome or monosomy 3. RFLP analysis showed loss of heterozygosity (LOH). The authors suggested that RCC may arise from the deletion of a 'recessive cancer gene.'
Van der Hout et al. (1988) compared chromosome 3 markers in normal and tumorous nephrectomy specimens from 7 RCC patients. Three patients were not informative because of homozygosity at all loci studied. One patient showing heterozygosity at 3q in normal tissue had a tumor that remained heterozygous. In 3 patients the tumor showed LOH for a short arm marker at 3p21; in 1 of them, heterozygosity for a second short arm marker was also lost. A second of these 3 patients retained heterozygosity for the second short arm marker, as well as for a long arm marker, suggesting a chromosomal breakpoint between the loci for the 2 short arm markers.
In a study of the karyotype of 75 sporadic, nonpapillary renal cell carcinomas, Kovacs and Frisch (1989) found aberration of chromosome 3 in 71 cases; see 144700. The rearrangement of chromosome 3p was the only change in 13 tumors. Abnormalities of chromosome 5 resulting in trisomy for the 5q22-qter region were found in 36 cases, whereas the loss of the 14q22-qter segment was observed in 34 tumors.
By studying LOH in 41 matched tumor/normal kidney tissue pairs, van der Hout et al. (1991) limited the commonly deleted part of 3p to the region between THRB (190160) in 3p24.3 and D3S2 in 3p21. The regions on 3p thought to be involved in the von Hippel-Lindau syndrome and in hereditary renal cell carcinoma are both outside this smallest region of overlapping deletions. Unlike some other tumor types, RCC does not show multiple allelic losses on a number of chromosomes; LOH is restricted mainly to chromosome 3.
Erlandsson et al. (1988) compared the age distribution of 51 hereditary and 56 sporadic cases of RCC sampled from the literature. The age-incidence curve of the hereditary RCC was compatible with a single event, whereas the sporadic tumors arose as predicted from a 2-hit curve. Thus, in analogy with Knudson's original prediction for retinoblastoma and Wilms tumor, RCC appears to arise by the loss of a recessive cancer gene, probably located in band 3p14.2.
Anglard et al. (1992) found LOH on 3p in 25 cell lines derived from 28 informative nonpapillary forms of RCC. Deletion-mapping analysis showed retention of the distal locus D3S18 in one of the RCC lines, further localizing the putative tumor suppressor gene.
Ogawa et al. (1992) found an inverse relationship between allelic losses at chromosome 17p in renal cell carcinoma and allelic losses at 3p: none of the 5 informative RCCs with allelic losses at 17p showed allelic losses at 3p. Conversely, 17 of 25 informative RCCs with retention of 17p alleles lost alleles at 3p. They demonstrated that allelic losses at 17p were infrequent in the clear cell type of RCC, whereas allelic losses at 17p were significantly more frequent in the granular cell type of RCC. Ogawa et al. (1991) had previously reported that allelic losses at 3p were specific to the clear cell type of RCC.
Rodriguez-Perales et al. (2004) characterized a 5-kb microdeletion at the chromosome 3 breakpoint in a family with a translocation t(3;8)(p14.2;q24.2) that segregated with conventional RCC. In this gene-poor region, only LRIG1 (608868), which was located more than 200 kb away from the breakpoint, showed expression in any of the tested tissues, including normal adult and fetal kidney, sporadic kidney tumors, and tumor samples from the proband's family. The authors proposed that a 3-step model of tumor development (translocation, loss of the 3p chromosome, and mutation in a tumor suppressor gene located within that region) could be the biological mechanism that takes place in this familial form of conventional RCC.
In a retrospective analysis of 123 patients from 55 families with von Hippel Lindau syndrome (193300), including 13 with complete germline deletion of the VHL gene (608537) and 42 with partial gene deletions, Maranchie et al. (2004) observed a paradoxically lower prevalence of renal cell carcinoma in those with complete gene deletions. RCC occurred more frequently in patients with partial germline VHL deletions relative to complete deletions (48.9% vs 22.6%, p = 0.007). Deletion mapping demonstrated that development of RCC had an even greater correlation with retention of HSPC300 (C3ORF10; 611183), located within the 30-kb region of 3p immediately telomeric to the VHL gene (52.3% vs 18.9%, p less than 0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC.
Cascon et al. (2007) found that 6 of 8 patients with VHL without RCC had large germline deletion of the VHL gene including deletion of HSPC300. In contrast, 9 of the 10 with RCC had retention of the HSPC300 gene. Analysis of 9 sporadic RCC tumors showed that all retained an HSPC300 allele. Studies in RCC tumor cell lines showed that genetic depletion of HSPC300 resulted in cytoskeleton abnormalities and defects in cytokinesis, indicating an alteration in actin kinetics and suggesting that tumor cell proliferation was compromised in the absence of HSPC300. Cascon et al. (2007) concluded that loss of the HSPC300 gene confers protection against renal clear cell carcinoma.
In a brother and sister diagnosed with bilateral clear cell RCC in their forties, Poland et al. (2007) detected a constitutional balanced translocation t(3;8)(p14;q24.1). This was the same translocation reported in the family studied by Cohen et al. (1979) and Gemmill et al. (1998). Poland et al. (2007) reported that, as in the case of the previously reported family, the translocation disrupted the FHIT gene on chromosome 3p14 and the TRC8 gene (603046) on chromosome 8q24.1. FISH analysis demonstrated that the TRC8 signal was absent in a set of diploid and pseudotetraploid cells from the tumor. Additionally, a heterozygous frameshift mutation in the VHL gene was found in the tumor. Poland et al. (2007) concluded that inactivation of TRC8 may cooperate with VHL mutations during the development and progression of clear cell RCCs.
Translocation t(2;3)
Koolen et al. (1998) identified a familial case of renal cell carcinoma. Four patients over 3 generations developed nonpapillary RCCs, and 1 patient was diagnosed with squamous bladder carcinoma. Cytogenetic analysis showed that all these patients and several unaffected members carried a balanced t(2;3)(q35;q21) translocation. To elucidate the role of this novel chromosome 3 translocation in RCC development, Bodmer et al. (1998) performed allele segregation, loss of heterozygosity, and mutation analyses of various normal tissues and primary tumor samples. They demonstrated loss of the translocation-derivative chromosome 3 in 5 independent renal cell tumors of the clear-cell type, obtained from 3 members of the family carrying the constitutional translocation. In addition, analysis of the VHL gene revealed distinct insertion, deletion, and substitution mutations in 4 of the 5 tumors tested. On the basis of these findings, Bodmer et al. (1998) concluded that, in this familial case, an alternative route for RCC development was implied. In contrast to the first hit in the generally accepted 2-hit tumor-suppressor model proposed by Knudson, the familial translocation in this case may act as a primary oncogenic event, leading to nondisjunctional loss of the derivative chromosome 3 harboring the VHL tumor-suppressor gene. Mutations in the VHL gene on the other chromosome would result in subsequent tumor formation. The risk of developing renal cell carcinoma may be correlated directly with the extent of somatic (kidney) mosaicism resulting from the loss of the der(3) chromosome.
Podolski et al. (2001) analyzed a balanced constitutional chromosome translocation, t(2;3)(q33;q21), associated with multifocal clear cell renal carcinoma in a Polish family. The site of the break was similar to that in the family reported by Bodmer et al. (1998) and Koolen et al. (1998). Physical mapping showed that the 3q break was in 3q13 in the Polish family, possibly near the border with 3q21. Physical mapping illustrated that the 2q break was closely telomeric to the 2q31 FRA2G site, consistent with the G-band assignment.
Druck et al. (2001) identified a novel gene, DIRC1 (606423), at the chromosome 2q33 breakpoint of the RCC-related translocation t(2;3)(q33;q21) reported by Podolski et al. (2001).
Bodmer et al. (2002) identified the DIRC2 gene (602773) at the chromosome 3q21 breakpoint of the familial RCC-associated t(2;3)(q35;q21) translocation. The breakpoint was within intron 7 of the DIRC2 gene. Since they detected normal DIRC2 transcripts in t(2;3)-positive tumor cells and in several sporadic cases of RCC, they concluded that the observed gene disruption may result in haploinsufficiency and, through this mechanism, the onset of tumor growth.
Van Erp et al. (2003) initiated a survey of all known Dutch families known to segregate the chromosome 3 translocations for the occurrence of renal cell carcinomas, and also for the establishment of refined risk estimates. Four novel tumors had been detected: 3 in a t(2;3)(q35;q21) family; 2 of the tumors (bilateral RCC) being in a 30-year-old translocation carrier (Bodmer et al., 2002); and 1 in a 67-year-old member of the t(3;6)(q12;q15) family (Eleveld et al., 2001). Van Erp et al. (2003) provided a table of the general features of the 7 RCC families with constitutional chromosome 3 translocations, and a diagram of chromosome 3 showing the location of the breakpoints in 93 Dutch families with chromosome 3 translocations and in somatic chromosome 3 translocations found in 157 sporadic RCCs.
Bodmer et al. (2003) identified the DIRC3 gene (608262) at the chromosome 2q35 breakpoint in the family with RCC and the t(2;3)(q35;q21) translocation. They determined that the translocation resulted in the formation of a DIRC3-HSPBAP1 (608263) fusion transcript. The breakpoints in both genes were intronic, and the fusion created a transcript where the first 2 exons of DIRC3 replaced exon 1 of HSPBAP1. The putative truncated HSPBAP1 protein retained its JmjC and Hsp27 (602195)-interacting domains, which are associated with chromatin remodeling and stress response, respectively.
To determine if phenotypic differences in the family carrying the RCC-associated t(2;3)(q35;q21) translocation were due to minor differences in the chromosomal breakpoints, Bodmer et al. (2003) examined the breakpoints in 9 different translocation carriers in the family, including 2 who had developed renal cancer, 1 who had developed bladder cancer, and 6 who had not developed cancer. In all translocation carriers, the chromosome 3 breakpoint coincided with a 3.4 kb-deletion, and the chromosome 2 breakpoint coincided with a 34-bp deletion; no differences could be detected in any of these breakpoint fragments.
Other Cytogenetic Abnormalities
Pathak et al. (1982) reported an acquired balanced 3;11 translocation in tumor cells from a patient with a normal constitutional karyotype and a history of renal cell carcinoma in the paternal grandfather and a paternal uncle.
Miles et al. (1988) found trisomy or tetrasomy of chromosome 7 as the most frequent abnormality in nonfamilial renal cell carcinoma, being present in tumors from 15 of 19 patients with cytogenetically abnormal neoplasms. An abnormal chromosome 3 was found in 10 of the cases: 2 were trisomic for chromosome 3; 2 were monosomic; 3 were hyperdiploid; and 3 had interstitial deletions with breakpoints clustered from p11 to p25. Kovacs and Brusa (1988) could find no correlation between breakpoints on 3p or 5q and fragile sites on those chromosome arms.
In a study of the karyotype of 75 sporadic, nonpapillary renal cell carcinomas, Kovacs and Frisch (1989) abnormalities of chromosome 5 resulting in trisomy for the 5q22-qter region were found in 36 cases, whereas the loss of the 14q22-qter segment was observed in 34 tumors.
Kuiper et al. (2003) collected 3 cases of RCC from patients 14 to 42 years of age, wherein a somatic t(6;11)(p21;q13) translocation was the sole cytogenetic abnormality in the tumor cells. Molecular analysis revealed fusion of the TFEB gene (600744) on chromosome 6 to the Alpha gene (MALAT1; 607924) on chromosome 11. The Alpha/TFEB fusion gene linked all coding exons of the TFEB gene to 5-prime upstream regulatory sequences of the Alpha gene. Alpha/TFEB mRNA levels were significantly upregulated in primary tumor cells as compared with wildtype TFEB mRNA levels in normal kidney samples, resulting in a dramatic upregulation of TFEB protein levels. The TFEB protein encoded by the Alpha/TFEB fusion gene was efficiently targeted to the nucleus. Kuiper et al. (2003) speculated that this resulted in severely unbalanced nuclear ratios of MITF (156845)/TFE subfamily members and that this imbalance may lead to changes in the expression of downstream target genes, ultimately resulting in the development of RCC.
MappingNonpapillary Renal Carcinoma 1 Locus
Evidence for a tumor suppressor gene in the 3p region proximal to the fragile histidine triad gene (FHIT; 601153) was shown by the functional studies of Sanchez et al. (1994), who transferred an intact human chromosome 3 and subsequently a centric fragment of 3p (encompassing the 3p14-q11 region) into a nonpapillary renal cell carcinoma (RCC) cell line. In all experiments, the 3p centric fragment mediated a dramatic tumor suppression and rapid induction of tumor cell death after subcutaneous injection of microcell hybrids in athymic nude mice. Physical mapping of suppressed and unsuppressed fragment-containing microcell hybrids, performed by Lott et al. (1998), limited the region containing the tumor suppressor locus, designated NRC1 ('nonpapillary renal carcinoma-1'), to within 3p12 and distinct from the gene (VHL; 608537) mutant in von Hippel-Lindau syndrome (193300). Lovell et al. (1999) reported the suppression of tumorigenicity of RCC cells in vivo after the transfer of the defined centric 3p fragment by microcell-mediated transfer into different histologic types of RCC. The results documented the functional involvement of NRC1 not only in different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillary RCC, a less frequent histologic type of RCC for which 3p loss of heterozygosity (LOH) and genetic aberrations have only rarely been observed. They also reported that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting the role of NRC1 as a more general mediator of in vivo growth control. This report demonstrated the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC1.
Teh et al. (1997) described 2 kindreds, 1 Australian and 1 French, with 9 cases of non-von Hippel Lindau nonpapillary clear cell renal cancer. Mutation analysis of the VHL gene and linkage analysis of flanking markers excluded VHL and the 3p14.2 region as the site of mutation.
Molecular GeneticsShimizu 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.
In an integrated molecular study of clear cell renal cell carcinoma involving more than 100 cases, Sato et al. (2013) identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures to determine their impact on tumor behavior. Defective VHL (608537)-mediated proteolysis was a common feature of clear cell renal cell carcinoma, which was caused not only by VHL inactivation but also by hotspot TCEB1 (600788) mutations, which abolished elongin C-VHL binding, leading to HIF accumulation. Other pathways and components recurrently mutated in clear cell renal cell carcinoma identified included PI3K (see 171834)-AKT (164730)-mTOR (601231) signaling, the KEAP1 (606016)-NRF2 (600492)-CUL3 (603136) apparatus, DNA methylation, p53 (191170)-related pathways, and mRNA processing.
Benusiglio et al. (2015) sequenced the PBRM1 gene in 35 unrelated patients with unexplained personal history of clear cell renal cell carcinoma (ccRCC) and at least 1 affected first-degree relative. The authors identified a germline frameshift mutation (606083.0001) in 1 patient. The patient's mother, his sister, and niece also had ccRCC, and the mutation segregated with the disease in the family. Somatic studies supported these findings, as both loss of heterozygosity for the mutation and loss of protein expression in renal tumors was identified.
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.
Genotype/Phenotype CorrelationsAlthough 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.
Biochemical FeaturesKrambeck et al. (2006) found that 153 (59%) of 259 tissue specimens from patients with renal cell carcinoma expressed the B7H4 molecule (608162), a coregulatory molecule that inhibits T-cell activity. Ninety-four (36%) cancer specimens expressed both B7H4 and B7H1 (605402), a similar molecule. Expression of both molecules was associated with increased tumor aggressiveness and increased risk of death. The findings suggested that expression of these molecules by tumor cells may impair host immunity and facilitate tumor progression.
Jiang et al. (2006) found that tumor expression of IMP3 (IGF2BP3; 608259) was greatly was associated with metastasis in clear cell RCC. Among 371 patients with localized clear cell RCC, those with IMP3 tumor expression had a significantly lower 5-year metastasis-free survival than those with IMP3-negative tumors (44% vs 98% for stage I; 41% vs 94% for stage II; and 16% vs 62% for stage III). IMP3 expression was also associated with reduced 5-year overall survival. These findings were replicated by Hoffmann et al. (2008) who studied 716 clear cell RCC specimens and found that 213 (29.8%) of 716 tumors expressed IMP3, which was associated with advanced stage and grade of primary tumors as well as other adverse features, including coagulative tumor necrosis and sarcomatoid differentiation. After multivariate adjustment, positive IMP3 expression was still associated with a 42% increase in the risk of death from RCC. Among those with initially localized disease, positive IMP3 expression was associated with a 4.71-fold increased risk of distant metastases.
Jiang et al. (2008) found that 40 (12%) of 334 RCCs, including 254 papillary and 80 chromophobic tumors, expressed IMP3. Positive IMP3 expression was significantly associated with later tumor stage and higher tumor grade. An analysis of patient outcomes showed that 28 of 317 with initially localized disease progressed to metastasis. Fifteen (45.5%) of the 33 patients with IMP3-positive tumors developed metastases compared to only 13 (4.6%) of the 284 patients with IMP3-negative tumors. Statistical analysis showed that those with initially localized IMP3-positive tumors were over 10 times more likely to have metastasis (risk ratio of 11.38; p less than 0.001), and were nearly twice as likely to die compared to patients with localized IMP3-negative tumors. The 5-year metastasis-free and overall survival rates were 64% and 58% for patients with IMP3-positive localized papillary and chromophobe RCCs compared to 98% and 85% for patients with IMP3-negative tumors, respectively. Jiang et al. (2008) concluded that IMP3 expression can be used as a prognostic biomarker for metastasis in all subtypes of renal cell carcinoma.
By microarray analysis, Liu et al. (2009) found high expression of the SPOP gene (602650) in up to 99% of human renal cell carcinomas, but not in normal kidney tissue, suggesting that it may be a specific tumor marker for renal cell carcinoma.
The Cancer Genome Atlas Research Network (2013) surveyed more than 400 clear cell renal carcinoma tumors using different genomic platforms and identified 19 significantly mutated genes. The PI3K/AKT pathway (see 164730) was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the histone 3 lysine-36 (H3K36) methyltransferase SETD2 (612778), and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodeling complex (PBRM1, 606083; ARID1A, 603024; SMARCA4, 603254) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the tricarboxylic acid cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of MIR21 (611020) and GRB10 (601523). The Cancer Genome Atlas Research Network (2013) concluded that remodeling cellular metabolism constitutes a recurrent pattern in clear cell renal cell carcinoma that correlates with tumor stage and severity and offers new views on the opportunities for disease treatment.
Li et al. (2014) used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that FBP1 (611570) was uniformly depleted in over 600 clear cell renal cell carcinoma (ccRCC) tumors examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. The data further indicated that FBP1 inhibits ccRCC progression through 2 distinct mechanisms: first, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cells of origin, thereby inhibiting a potential Warburg effect; second, in VHL (608537)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis, and the pentose phosphate pathway in a catalytic activity-independent manner by inhibiting nuclear HIF (see 603348) function via direct interaction with the HIF inhibitory domain. Li et al. (2014) concluded that this unique dual function of the FBP1 protein explains its ubiquitous loss in clear cell renal cell carcinoma, distinguishing FBP1 from previously identified tumor suppressors that are not consistently mutated in all tumors.
Other FeaturesLinehan et al. (1989) demonstrated that removal of leukocytes from disaggregated renal cell carcinomas improved the detection of allele loss in these carcinomas. The technique should be useful in allele deletion analysis of other solid tumors that are contaminated with host leukocytes.
HistoryFairchild et al. (1979) described a 29-year-old woman who had neuroblastoma during infancy, developed an extraadrenal pheochromocytoma at age 16 years, with subsequent hepatic recurrence, and was found to have multifocal renal cell carcinoma. Renal cell carcinoma and pheochromocytoma are combined in the von Hippel-Lindau syndrome, but there was no evidence in this patient or her family. The association of pheochromocytoma and neuroblastoma had, it seemed, not been previously noted. Schimke et al. (2010) reported 2 sibs of the patient reported by Fairchild et al. (1979) who developed paraspinal paragangliomas in adulthood, and a cousin of these sibs who died of metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. Genetic analysis identified a heterozygous mutation in the SDHB gene (V140F; 185470.0016), consistent with paragangliomas-4 (PGL4; 115310). There were 2 unaffected family members, suggesting decreased penetrance or a 'leaky' mutation. Schimke et al. (2010) noted the importance of family history in elucidating the etiology of this inherited disorder.
Animal ModelEveritt et al. (1992) described the Eker rat, a rodent model of hereditary cancer in which a single gene mutation predisposes them to bilateral multicentric renal cell carcinoma. The disorder bore similarities to von Hippel-Lindau disease. Splenic vascular proliferative lesions, including hemangiosarcoma, were seen in 23% of 14-month-old rats of both sexes that had renal tumors. At that age, 62% of female rats with renal cell tumors had sarcomas of the lower reproductive tract of probable smooth muscle origin. In this rat model of human renal carcinoma, Walker et al. (1992) identified a germline mutation at a tumor susceptibility locus that caused a 70-fold increase in susceptibility to chemical carcinogenesis. A carcinogen that targeted both renal epithelial and mesenchymal cells caused an increase in tumors of epithelial origin in susceptible animals but no increase in carcinogen-induced mesenchymal tumors.
Rats that are heterozygous for the so-called Eker mutation develop spontaneous RCCs between 4 and 12 months of age. When homozygous, the mutation is lethal prenatally at 9 to 10 days of gestation. At the histologic level, renal carcinomas in the Eker rat develop through multiple stages from early preneoplastic lesions (e.g., atypical tubules) to adenomas in virtually all heterozygotes by the age of 1 year. Hino et al. (1993) demonstrated that ionizing radiation induces additional tumors in a linear dose-response relationship, suggesting that in heterozygotes 2