Allelic imbalance on chromosomes 13 and 17 and mutation analysis of BRCA1 and BRCA2 genes in monozygotic twins concordant for breast cancer

To study genetic changes associated with the development of breast cancer a nd the extent of its hereditary predisposition, paraffin-embedded tissue sa mples were obtained from monozygotic twin pairs concordant for breast cance r through the linked Swedish Twin and Cancer Registries. DNA samples extrac ted from the matched tumour and normal tissues of nine twin pairs were anal ysed for allelic imbalance using a series of microsatellite markers on chro mosomes 13 and 17, containing loci with known tumour suppressor genes. Mult iple losses of constitutional heterozygosity (LOH), consistent with a loss of large genomic region, the whole chromosome or chromosome arm, was found in at least three pairs of twins. One double mitotic crossover was identifi ed in one tumour sample in a pair concordant for LOH at multiple loci on bo th chromosomes. Recombination breakpoints were mapped to regions delineated by D13S218 and D13S263, and D13S155 and D13S279, respectively, In general, no genetic effect of losing the same allele within a twin pair was found. However, for one marker at chromosome 13 (D13S328, between the BRCA2 and th e Rb-1 loci) and two markers on chromosome 17 (D17S786, distal to the p53 l ocus, and D17S855, an intragenic BRCA1 marker) the proportion of twin pairs with the same LOH was significantly higher than expected. These regions ma y reflect hereditary genomic changes in our sample set. In addition, tumour DNA samples from a subset of 12 twin pairs were analysed for BRCA1 and BRC A2 mutations using exon-by-exon single-strand conformation polymorphism ana lysis. Two unclassified BRCA2 variants, with a putative pathogenic effect, were identified, but no pathogenic alterations were found in the BRCA1 gene .