Abstract for presentation at 11th International Congress of Human Genetics

Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial variability in the penetrance of breast cancer in BRCA/2 mutation carriers, ranging from 40-85% percent depending on the cohort studied. Statistical variation, sampling bias or genetic heterogeneity is few variables that complicate the mapping of genetic modifiers of BRCA penetrance. To date relatively few environmental-gene interactions have been found to modify penetrance associated with specific BRCA mutations. We performed a whole genome-wide linkage disequilibrium (LD) mapping using Affymetrix 10K GeneChip arrays to localize BRCA2 modifier genes. To reduce genetic heterogeneity, all the samples in this study were of Ashkenazi Jewish ancestry, a population isolate in which 2.5% of unselected individuals carry one of three ancient founder mutations (BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT). We compared the frequencies of genotypes and haplotypes in 10 early onset (<40) breast cancer affected versus 12 unaffected elderly (>65) individuals, all carriers of BRCA2 6174delT mutation. After haplotype analysis, we have identified two candidate breast cancer modifying loci 1) region on chromosome 12 spanning approximately 1.5Mbp between markers TCS 563190 and TSC884792 (p=0.001) 2) region on chromosome 22 between markers TSC898055 and TSC191209 spanning 3.1Mbp of genomic size (p=0.0013). The presence of highly conserved haplotypes observed in 12 old (>65) non affected BRCA2 carriers indicates the possibility of protective modifier gene in these regions in unaffected elderly carriers. Due to a high density of candidate genes in these two regions further fine-mapping by higher density SNP map will be needed to refine the minimal size of the haplotype block corresponding to a putative BRCA modifier gene.