Analysis of the TSC1 and TSC2 genes in sporadic renal cell carcinomas.

L Parry,S C Clifford,C Morrissey,J H Maynard,J P Cheadle,J R Sampson,A Patel,E R Maher

doi:10.1054/bjoc.2001.2072

L Parry, S C Clifford + Show 6 more

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https://doi.org/10.1054/bjoc.2001.2072

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Abstract

The genetic events involved in the aetiology of non-clear-cell renal cell carcinoma (RCC) and a proportion of clear cell RCC remain to be defined. Germline mutations of the TSC1and TSC2genes cause tuberous sclerosis (TSC), a multi-system hamartoma syndrome that is also associated with RCC. We assessed 17 sporadic clear cell RCCs with a previously identified VHLmutation, 15 clear-cell RCCs without an identified VHLmutation and 15 non-clear-cell RCCs for loss of heterozygosity (LOH) at chromosomes 9q34 and 16p13.3, the chromosomal locations of TSC1and TSC2. LOH was detected in 4/9, 1/11 and 3/13 cases informative at both loci. SSCP analysis of the whole coding region of the retained allele did not reveal any cases with a detectable intragenic second somatic mutation. Furthermore, RT-PCR analysis of TSC1and TSC2on total RNA from 8 clear-cell RCC cell lines confirmed expression of both TSC genes. These data indicate that biallelic inactivation of TSC1or TSC2is not frequent in sporadic RCC and suggests that the molecular mechanisms of renal carcinogenesis in TSC are likely to be distinct. © 2001 Cancer Research Campaignhttp://www.bjcancer.com http://www.bjcancer.com

Highlights

The molecular genetic events leading to renal cell carcinoma (RCC) are not fully understood
Recurrent regions of deletion on chromosomes 3p, 4q, 6q, 8p, 9p and amplifications on 17q and Xq have been revealed by comparative genomic hybridisation (CGH) (Verdorfer et al, 1998; Bissig et al, 1999) and loss of heterozygosity (LOH) studies (Thrash-Bingham et al, 1995), as have alterations on 2, 3, 9–12, 16, 17 and 18 by restriction landmark genomic scanning (RLGS) (Cho et al, 1998a,b)
Several known and putative tumour suppressor genes (TSGs) map to 3p and both the von Hippel–Lindau (VHL) (Latif et al, 1993) TSG and further gene(s) at 3p12–p21 have been implicated in clear cell RCC

Summary

Introduction

The molecular genetic events leading to renal cell carcinoma (RCC) are not fully understood. Several known and putative tumour suppressor genes (TSGs) map to 3p and both the von Hippel–Lindau (VHL) (Latif et al, 1993) TSG and further gene(s) at 3p12–p21 have been implicated in clear cell RCC. VHL is mutated, deleted or hypermethylated in up to 70% of sporadic clear cell RCCs in addition to von Hippel–Lindau disease associated renal cell carcinoma (Prowse et al, 1997), but does not appear to play a significant role in papillary or other non-clear-cell cancers (Foster et al, 1994; Gnarra et al, 1994; Herman et al, 1994; Shuin et al, 1994; Clifford et al, 1998). Inactivation of 3p12–p21 TSG(s) has been implicated in most clear-cell RCC irrespective of VHL status, and to date no differences in molecular pathology have been identified between clear-cell RCC with and without VHL inactivation (Clifford et al, 1998, 1999)

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