Foulkes, William David; (1994) A molecular genetic analysis of ovarian carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Ovarian carcinoma (OC) is the commonest gynaecological cause of death in the Western world. As a step to new diagnostic and therapeutic approaches to this cancer, I aimed to identify genes that might be implicated in the initiation and progression of the disease. I collected more than 80 paired tumours and lymphocytes and applied molecular genetic methods to analyse the tumours for genomic alterations that underlie the disease process. Loss of heterozygosity (LOH) was used to try to localise regions that may contain tumour suppressor genes, as a prelude to their identification. During the course of this work, it was established that a small proportion of OC can be explained by an unknown, dominantly inherited gene (BRCA1) that maps to chromosome 17q12-21. According to models of inherited cancer, it is likely that the causative genes will be implicated in both sporadic and inherited cancers of the same type. Therefore, using LOH, I subjected chromosome 17 to extensive analysis in sporadic OC. A high frequency of LOH (75%) was found, supporting the linkage data in familial OC. This loss always included BRCA1, but in more than 80% of cases, all markers showed LOH, so that further localisation was not possible. Mutation analysis of BRCA1-candidate genes such as 1A1.3B was carried out. So far, no tumour-specific mutations have been detected. Other genes may be aberrant in somatic cells, and evidence for the presence of such tumour suppressor genes was found on chromosomes 5, 6 and 11, again by LOH. The APC gene, on 5q21 was subjected to extensive mutation analysis in OC and excluded. On chromosome 6, LOH (67% overall) commonly affects the whole of 6q, but our data, taken together with other groups' findings, supported a 6q27 localisation for a putative tumour suppressor gene. Our LOH data on chromosome 11q suggest that the critical region is 11q23.3-qter. When all the data from the different chromosomes studied were combined, the frequency of LOH increased as the grade of tumour increased. Of the tumours analysed, LOH on any chromosome was most common in grade 3 serous or undifferentiated carcinomas. This work shows that there are at least four regions of the genome that may contain tumour suppressor genes of relevance to OC, and forms a foundation for the cloning and functional analysis of these genes.

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