Family and tumour studies in breast and oesophageal cancer

Kelsell, David Peter (1997). Family and tumour studies in breast and oesophageal cancer. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000d525

Abstract

This study focussed on two areas in the field of cancer susceptibility. The initial area was the genetic analysis of a recently mapped breast cancer susceptibility locus, BRCAl, in a number of breast and breast-ovarian cancer families. In the largest of the ICRF families studied (BOV3), linkage to the long arm of chromosome 17 was confirmed and a number of recombinants were identified. One such cross-over event enabled the reduction of the interval harbouring BRCAI to a region estimated to be between 1-1.5 Mh. During the course of this study, a second gene for breast/ovarian cancer predisposition, BRCA2, had been assigned to a 6 cM region at 13q12-13.Towards the identification of this gene, a YAC contig was constructed spanning the published minimal genetic interval for BRCA2. This contig provided a framework for the identification of BRCA2. Allele loss studies were also performed and indicated that BRCA1 acts as a tumour suppressor. Analysis of familial and sporadic infiltrating ductal grade 3 breast carcinomas revealed a pattern of combined loss or retention of BRCAI and BRCA2. This supports a role for both genes in the development of thistumour type. The other area of study was the genetic analysis of a group of autosomal dominant skin diseases, termed the non-epidermolytic palmoplantar keratodermas. This study demonstrated genetic heterogeneity between three forms of NEPPK: diffuse, punctate and focal. Genetic heterogeneity was also established between families presenting with clinically similar forms of focal NEPPK. Mutations in thetype I keratin on 17q12-21, KRT16, were identified as the genetic basis of focal NEPPK in a pedigree without associated susceptibility to oesophageal cancer. In the pedigrees with a striking association between focal NEPPK and oesophageal cancer susceptibility, the region harbouring this disease locus (TOC) was refined to a lcMregion on 17q24-25.