Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat

Compared with the general population, women who have inherited a germline m utation in the BRCA1 gene have a greatly increased risk of developing breas t cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothes ize that other genes, particularly those involved in endocrine signaling, m ay modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the and rogen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-respon sive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without b reast cancer. We found that women were at significantly increased risk of b reast cancer if they carried at least one AR allele with greater than or eq ual to 28 CAG repeats. Women who carried an AR-CAG allele of greater than o r equal to 28, greater than or equal to 29, or greater than or equal to 30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women wh o did not carry at least one such allele. All 11 women in our sample who ca rried at least one AR-CAG allele with greater than or equal to 29 repeats h ad breast cancer. Our results support the hypothesis that age at breast can cer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen sign aling may affect the risk of BRCA1-associated breast cancer.