Frequent somatic loss of BRCA1 in breast tumours from BRCA2 germ-line mutation carriers and vice versa

Breast cancer susceptibility genes BRCA1 and BRCA2 are tumour suppressor ge nes the alleles of which have to be inactivated before tumour development o ccurs. Hereditary breast cancers linked to germ-line mutations of BRCA1 and BRCA2 genes almost invariably show allelic imbalance (Al) at the respectiv e loci. BRCA1 and BRCA2 are believed to take part in a common pathway in ma intenance of genomic integrity in cells. We carried out Al and fluorescence in situ hybridization (FISH) analyses of BRCA2 in breast tumours from germ line BRCA1 mutation carriers and vice versa. For comparison, 14 sporadic br east tumours were also studied. 8 of the 11 (73%) informative BRCA1 mutatio n tumours showed Al at the BRCA2 focus. 53% of these tumours showed a copy number loss of the BRCA2 gene by FISH. 5 of the 6 (83%) informative BRCA2 m utation tumours showed Al at the BRCA1 locus. Half of the tumours (4/8) sho wed a physical deletion of the BRCA1 gene by FISH. Combined allelic loss of both BRCA1 and BRCA2 gene was seen in 12 of the 17 (71%) informative hered itary tumours, whereas copy number losses of both BRCA genes was seen in on ly 4/14 (29%) sporadic control tumours studied by FISH. In conclusion, the high prevalence of Al at BRCA1 in BRCA2 mutation tumours and vice versa sug gests that somatic events occurring at the other breast cancer susceptibili ty gene locus may be selected in the cancer development. The mechanism resu lting in Al at these loci seems more complex than a physical deletion. (C) 2001 Cancer Research Campaign.