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.


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.

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