USING GENE CARRIER PROBABILITY TO SELECT HIGH-RISK FAMILIES FOR IDENTIFYING GERMLINE MUTATIONS IN BREAST-CANCER SUSCEPTIBILITY GENES

Germline mutations in highly penetrant autosomal dominant genes explai n about 5% of all breast cancer, and heritable mutations in the BRCA1 breast and ovarian cancer susceptibility gene account for 2-3% of brea st cancer in the general population. Nevertheless, the presence of suc h mutations is highly predictive of disease development. Since screeni ng for mutations is still technically laborious, we investigated wheth er the prior probability of being a carrier of a dominant breast cance r susceptibility gene in the youngest affected family member could be used to identify families in which the probability of finding a mutati on is sufficiently high. Sixty German families with three or more case s of breast/ovarian cancer with at least two cases diagnosed under the age of 60 were screened for mutations by SSCP/CSGE and subsequent dir ect sequencing. Thirteen germline truncating/splicing mutations in BRC A1 were found in 33% (6/18) of the breast-ovarian cancer families and in 17% (7/42) of breast cancer only families. All the families showing mutations in BRCA1 had carrier probabilities of 0.65 or higher. In fa milies with prior carrier probabilities above 0.6, the proportion dete cted was 0.46 in breast-ovarian cancer families and 0.26 in breast can cer only families. The average age at diagnosis of breast or ovarian c ancer in families with BRCA1 mutations was 41.9 years and significantl y lower than in families without mutations (p<0.05). Mutation carriers and obligate carriers were also found to have cancers at other sites. The probability of being a susceptibility gene carrier, taking into a ccount the complete pedigree information, allows uniform characterisat ion of all types of families for identifying those in which mutation a nalysis for BRCA1/2 is warranted. However, prior probabilities calcula ted using this method can be reduced when the correlation between geno type and phenotype is imperfect. A larger series of families needs to be investigated in this fashion to provide better estimates of the det ection rate for different ranges of carrier probabilities.