Involvement of multiple loci on chromosome 3 in renal cell cancer development.
In renal cell carcinoma (RCC), mostly occurring as sporadic cases, the short arm of chromosome 3 is a frequent target of deletion events. Taking into account cytological classifications of RCC, the deletions appear to be characteristic of clear cell or nonpapillary RCC only. This subtype constitutes most sporadic RCC and RCC as part of the Von Hippel-Lindau disease caused by germline mutations of VHL at 3p25. In a proportion of sporadic tumours, somatic mutations of VHL occur, again only in clear cell or nonpapillary RCC. However, in a sizable proportion of sporadic clear cell RCC, VHL mutations are absent. Therefore, a role for VHL in RCC development in general seems unlikely. Familial papillary RCC is not linked to chromosome 3. A rat model of hereditary RCC, the EKER rat, is associated with a germline mutation of the rat homologue of the tuberous sclerosis gene on human chromosome 16. Analysis of allelic losses of chromosome 3 in 143 highly informative sporadic tumours published in the literature points to a small segment of 3p21.3 as a candidate tumour-suppressor region. A 2-Mb fragment containing this segment suppresses tumourigenicity when present in mouse fibrosarcoma cells. A similar effect could be attributed to the region 3p12-p14 on the basis of results from its introduction into an RCC cell line. The responsible gene should not be sought at 3p14 translocation breakpoints segregating with RCC in a few rare families because there is evidence that RCC in these cases is due to events involving VHL or another gene distal to the breakpoint. FHIT is also an unlikely candidate according to observations comparing RCC and a variety of normal tissues. Results of an analysis of sporadic patients with multiple renal tumours indicate an association of allelic losses of the VHL and 3p12-p14 regions with adenomas and suggest that losses of the 3p21 region are necessary for malignant development to clear cell or nonpapillary RCC.
van den Berg
A
A
Department of Medical Genetics, University of Groningen, The Netherlands.
Buys
C H
CH
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002893:Chromosomes, Human, Pair 3; D030342:Genetic Diseases, Inborn; D006579:Heterozygote; D006801:Humans; D006867:Hydrolases; D051379:Mice; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured; D006623:von Hippel-Lindau Disease / Q000235:genetics
D011506:Proteins; C097552:histidine triad protein; D006867:Hydrolases; D017027:Protein Tyrosine Phosphatases