Foster, Keith; (2002) Molecular genetic analysis of non familial renal cell carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Human cancers are caused by mutations affecting the products of oncogenes, tumour suppressor genes and DNA repair genes. Identification of tumour suppressor genes that give rise to sporadic cancers has often been achieved by isolating rare familial cancer genes via a reverse genetic approach. Loss of heterozygosity (LOH) studies have suggested that somatic mutations of a tumour suppressor gene or genes on 3p are critical in the pathogenesis of non familial renal cell carcinoma (RCC). Different studies have implicated differing critical loci. To further investigate the role that 3p genes may have in the tumourigenesis of sporadic RCC, 55 paired normal-tumour DNA's were analysed for allele loss, and at regions of known or putative tumour suppressor genes on chromosomes 5, 11, 17 and 22. 64% (35/55) of informative tumours displayed LOH of at least one or more loci on 3p, compared with 13% at the p53 locus and 6% at 17q21. LOH at 5q21 and 22q was uncommon. The LOH study identified three critical regions of loss on chromosome 3, at 3p25-26, 3p21 and at 3p12-14. The von Hippel Lindau (VHL) tumour suppressor gene was isolated in 1993. It maps to chromosome 3p25-26, coincident with a region of LOH. VHL disease manifests as a variety of benign and malignant neoplasms, and is the most common cause of familial RCC. The role that mutations of the VHL gene may have in the pathogenesis of sporadic RCC was investigated. 99 primary RCC were analysed for SSCP and heteroduplex formations. Somatic mutations were identified in 46% (30/65) sporadic RCC's with 3p LOH and in 3% (1/34) with no 3p LOH. Histology was available for 59 tumours: 42% (18/43) of RCC with a clear cell phenotype had VHL mutations, whereas none of 16 with a non clear cell phenotype (8 chromophilic, 3 chromophobic, and 5 oncocytomas) had VHL mutations (χ2=7.77, p<0.025). These results confirm that mutations in the VHL gene are events that initiate the development of RCC. 3p allele loss is a frequent event in gonadal tumours. 60 gonadal (36 ovarian and 24 testicular) tumours were analysed for VHL gene mutations and 3p allele loss. 3p LOH was detected in 38% (10/26) of informative ovarian and 56% (7/13) testicular tumours, but no VHL mutations were found. This suggests that chromosome 3p tumour suppressor gene(s) other than VHL are involved in gonadal tumourigenesis.

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