ABSENCE OF METHYLATION OF CPG DINUCLEOTIDES WITHIN THE PROMOTER OF THE BREAST-CANCER SUSCEPTIBILITY GENE BRCA2 IN NORMAL-TISSUES AND IN BREAST AND OVARIAN CANCERS

Germline mutations of the BRCA2 gene on chromosome 13q12-q13 predispos e to the development of early-onset breast cancer and ovarian cancer. Loss of heterozygosity detected using chromosome 13q markers in the vi cinity of BRCA2 is observed in most cancers arising in carriers of ger mline BRCA2 mutations and also in 30-50% of sporadic breast and ovaria n cancers. However, somatic mutations of BRCA2 are extremely rare in s poradic cancers. We have examined the hypothesis that expression of th e BRCA2 gene may be suppressed in sporadic breast cancers by a mechani sm that is associated with increased methylation of cytosine residues in the promoter region. Using a Hpall/Mspl digestion-polymerase chain reaction based assay, the presence of 5-methylcytosine in three CpG di nucleotides within the BRCA2 promoter was assessed in 18 breast or ova rian cancer cell lines, in an SV40 large T antigen immortalized cell l ine derived from normal breast epithelial cells, in 64 primary sporadi c breast cancers and peripheral blood leucocytes from these cases and in a number of other normal human tissues. Methylation was not detecte d in any of the tissues examined, suggesting that this mechanism of tr anscriptional repression is unlikely to explain the absence of somatic mutations in sporadic cancers.