CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers

Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carrier s suggests that other genetic polymorphisms may modify the cancer risk in c arriers. A previous study has suggested that BRCA1 carriers with longer len gths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 16 6 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses wer e conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estimates based on the Breast Cancer Lin kage Consortium (BCLC) studies of multiple case families. and lower estimat es as suggested by population-based studies. We found no association of the CAG and GGC repeats with BC risk in either BRCA1/2 carriers or in the gene ral population. Assuming BRCA1/2 penetrance estimates appropriate to the As hkenazi population, the estimated RR per repeat adjusted for ethnic group ( Ashkenazi and non-Ashkenazi) was 1.05 (95% CI 0.97-1.17) for BC and 1.00 (9 5% CI 0.83-1.20) for ovarian cancer (OC) for CAG repeats and 0.96 (95% CI 0 .80-1.15) and 0.90 (95% CI 0.60-1.22) respectively for GGC repeats. The cor responding RR estimates for the unselected case-control series were 1.00 (9 5% CI 0.91-1.10) for the CAG and 1.05 (95% CI 0.90-1.22) for the GGC repeat s. The estimated relative risk of BC in carriers associated with greater th an or equal to 28 CAG repeats was 1.08 (95% CI 0.45-2.61). Furthermore, no significant association was found if attention was restricted to the Ashken azi carriers. or only to BRCA1 or BRCA2 carriers. We conclude that, in cont rast to previous observations. if there is any effect of the AR repeat leng th on BRCA1 penetrance, it is likely to be weak. (C) 2001 Cancer Research C ampaign http://www.bjcancer.com.