BRCA2 in familial and sporadic breast cancer
The breast cancer susceptibility gene BRCA2 is located on chromosome 13q 12-13. Using breast and ovarian cancers from a BRCA2-linked family, loss of the wild type BRCA2 allele was demonstrated in seven out of eight informative cases (87.5%) indicating that BRCA2 was a recessive oncogene. Analysis of 73 sporadic breast tumours and 12 breast cancer cell lines revealed loss of heterozygosity (LOH) in 22 (30%) of the primary tumours and seven (58%) of the breast cancer cell lines. However, it was not clear from these studies that the target for the observed LOH was the gene BRCA2 or RBl at chromosome 13q14 as the region ofLOH included both genes in all but a single case.
Despite the presence of elevated levels of LOH, several separate mutation screening studies of sporadic breast and ovarian tumours have shown that somatic mutations of BRCA2 in sporadic breast and ovarian cancer are very rare. To investigate the possibility that other mechanisms of BRCA2 allelic inactivation might be operative, the methylation status of a CpG island within the promoter region of BRCA2 was examined in 64 sporadic breast tumours and 18 breast and ovarian cancer cell lines. Three CpG dinucleotides within this island were unmethylated in all the normal tissue samples (lymphocytes) examined. These three CpG dinucleotides remained unmethylated in all the breast tumours examined. Moreover, expression of BRCA2 in breast and ovarian cancer cell lines was not obviously correlated with evidence of loss of heterozygosity. These analyses indicate that methylation of the promoter region of BRCA2 and possibly other mechanisms of transcriptional silencing are unlikely to be a common mechanism of gene inactivation in these tumours.
To investigate the prevalence of BRCA2 mutations, lymphocyte DNAs from a British, population-based series of 617 breast cancers diagnosed before age 45 were screened for mutations. Mutations were detected in 14 women ( 2.3%, 6/14 43% under age 35 and 8/14 57% age 36-45). This study and a parallel study of BRCA1 demonstrate that BRCA2 and BRCA1 make approximately equal contributions to early onset breast cancer in the UK. Moreover, although BRCA1 and BRCA2 account for breast cancer susceptibility in a substantial proportion of multiple case families, they only account for a small proportion of the overall familial risk conferred by an early onset case. This indicates the existence of other susceptibility genes that are more common but confer lower risks than BRCA1 and BRCA2.