Chambers, Julie Anne; (1998) Analysis of the breast cancer susceptibility gene (BRCA1) region in human and mouse. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Breast cancer is one of the most common diseases affecting women. A human breast cancer susceptibility gene, BRCAl, was localised to chromosome 17q in 1990, and worldwide efforts have focused on the isolation of this gene. This thesis describes the identification and characterisation of candidate genes within the region, using a number of different techniques. Following the isolation of the BRCA1 gene, breast and breast/ovarian cancer families were analysed for mutations in this gene, either by direct sequencing of the entire coding region or by screening for specific mutations using allele specific oligonucleotide hybridisation. These techniques identified mutations in the BRCAl gene in five families. The BRCA1 gene lies within a duplicated region on chromosome 17. Pseudo-copies of the 5' exons of BRCAl lie head to head with the NBR1 gene, whose function is unknown. Analyses of the BRCA1 and NBR1 genes in other species, in particular the mouse, are presented. Isolation of murine cDNA clones shows that NBR1 is highly conserved between the human and the mouse, whereas BRCA1 is less well conserved, but has several domains that are highly homologous with the human. The structure of the NBR1 gene is also well conserved, with exon/intron boundaries being largely the same in the two species. Analysis of mouse genomic clones reveals that this region is not duplicated in the mouse and that the Brca1 and Nbr1 genes lie head to head less than 1 kb apart. Studies on this promoter region, using a luciferase reporter gene assay system, are presented and suggest that the Brca1 gene and the Nbr1 gene may share a bidirectional promoter.

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