The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation.

Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity have been observed at high frequency in the nonpapillary form of sporadic renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) gene has been identified as a tumor suppressor gene for RCC at 3p25, and functional studies as well as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor genes for sporadic RCC. We have previously functionally defined a novel genetic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, distinct from the VHL gene, that mediates tumor suppression and rapid cell death of RCC cells in vivo. We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC. Results document the functional involvement of NRC-1 in not only 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 histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting a role for NRC-1 as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC-1.

Physical and functional mapping of a tumor suppressor locus for renal cell carcinoma within chromosome 3p12.

Using a functional genetic approach, we previously identified a novel genetic locus, NRC-1 (Nonpapillary Renal Cell Carcinoma 1), that mediated tumor suppression and rapid cell death of renal cell carcinoma (RCC) cells in vivo. For these experiments, a defined subchromosomal fragment of human chromosome 3p was transferred into a sporadic RCC cell line via microcell fusion, and microcell hybrid clones were tested for tumorigenicity in vivo. The results indicated functional evidence for a novel tumor suppressor locus within the 3p14-p12 interval known to contain the most common fragile site of the human genome (FRA3B), the FHIT gene, and the breakpoint region associated with the familial form of RCC. We now report the physical mapping of the NRC-1 critical region by detailed microsatellite analyses of novel microcell hybrid clones containing transferred fragments of chromosome 3p in the RCC cell background that were phenotypically suppressed or unsuppressed for tumorigenicity in vivo. The results limit the region containing the tumor suppressor locus within chromosome 3p12. The FHIT gene, FRA3B, and the familial RCC breakpoint region were excluded from the NRC-1 critical region. Furthermore, the NRC-1 locus falls within a well-characterized homozygous deletion region of 5-7 Mb associated with a small cell lung carcinoma cell line, U2020, suggesting that a more general tumor suppressor gene may reside in this region.

Surgical decision-making affected by clinical and genetic screening of a novel kindred with von Hippel-Lindau disease and pancreatic islet cell tumors.

OBJECTIVE: We report a unique, previously undescribed multigeneration kindred with von Hippel-Lindau (VHL) disease in whom clinical or genetic screening led to the detection of surgically resectable neoplastic disease in several family members. SUMMARY BACKGROUND DATA: Patients with VHL disease have a propensity to develop neoplasms of several different organ sites. Retinal angiomas, cerebellar and spinal hemangioblastomas, solid organ cysts, and renal carcinoma are common lesions; pheochromocytomas and pancreatic islet cell tumors occur less frequently but are important causes of morbidity and mortality. METHODS: A detailed pedigree was constructed based on clinical screening and family history that describes the development of pancreatic islet cell tumors in four of five female siblings. VHL mutation analysis was performed in an attempt to determine if genotype-phenotype correlations could be made in this interesting family. RESULTS: The age of onset of VHL-associated neoplasms for three affected siblings was in the third decade of life and in the fourth decade for the fourth sibling. The mother of the four siblings affected with pancreatic tumors developed bilateral pheochromocytomas in the seventh decade of life; she has no pancreatic or kidney tumors. We identified maternal transmission of a missense mutation in codon 238 in exon 3 of the VHL gene in the four affected siblings with pancreatic islet cell tumors. Mutation screening on unaffected family members showed no abnormalities in the VHL gene. Interestingly, one of the four affected siblings had no evidence of VHL on her initial clinical screening evaluation; however, she was followed closely because of her mutated VHL gene. Four years after initial screening, she developed two pancreatic islet cell tumors and a premalignant renal cyst. CONCLUSIONS: Clinical and genetic screening for VHL in this family had a significant impact on surgical management by detecting early-stage islet cell tumors or pheochromocytomas. Furthermore, we conclude that the preponderance of pancreatic islet cell tumors in this family cannot be explained by a strict genotype-phenotype correlation. This suggests that additional genetic abnormalities, possibly on chromosome 3p where the VHL gene is located, may be responsible for the variety of VHL-associated neoplasms.