Mavraki, Eleni; (1997) The genetics of susceptibility to breast cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

BRCA2 is an autosomal dominant, highly penetrant gene involved in familial breast and breast-ovarian cancer. Families with an inherited predisposition to these cancers were screened for linkage to the BRCA2 locus, previously mapped to 13q12-13. In two families showing linkage, two recombination events were identified which provided further support for the genetic marker D13S289 being the proximal boundary of the BRCA2 minimal region. Loss of heterozygosity analysis of one of the families gave additional evidence for a tumour suppressor role for BRCA2. Two Expressed Sequence Tags were mapped to the BRCA2 minimal region, providing candidate BRCA2 genes; however, during the course of this study the BRCA2 gene was identified by another group. Mutation analysis of the BRCA2 gene was performed in a number of families examined previously for linkage to the BRCA2 locus; a frame- shift mutation was identified in a single family containing a male affected individual. To investigate further the role of BRCA2 in male breast cancer, a number of randomly selected affected men were examined for BRCA2 germline mutations. Three mutations were identified; two frame- shifts and one missense mutation, suggesting that BRCA2 may be involved in a small but significant proportion of cases of male breast cancer. The concluding part of this study concerned the analysis of low penetrance alleles that may influence the risk of breast cancer in affected members of breast and breast-ovarian cancer families. Genotypes for the carcinogen metabolising enzymes Glutathione S-transferase mu-1 (GSTM1) and theta-1 (GSTT1) were determined and assessed in association with the age at onset of breast cancer in breast and breast-ovarian cancer families. No associations were observed between age at diagnosis of breast cancer and GSTT1 or/and GSTM1 genotypes.

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