Genetic Contribution of GADD45A to Susceptibility to Sporadic and Non-BRCA1/2 Familial Breast Cancers: A Systemic Evaluation in Chinese Populations.

Abstract

Abstract GADD45A is a candidate breast cancer susceptibility gene because its product participates in DNA repair and it is a downstream gene of p53 and BRCA1, both of which are breast cancer susceptibility genes. The genetic contribution of GADD45A to sporadic and familial breast cancer is still ambiguous. We screened germline mutation of GADD45A in 185 non-BRCA1/2 familial breast cancer patients, but no deleterious mutation was found. Seven single-nucleotide-polymorphisms were identified in a sub-sample. Five common variants (minor allele frequency (MAF)>10%) were genotyped for association analyses to scrutinize the relationship between breast cancer and polymorphisms in GADD45A in two independent population sets. In the first case-control study, a comparison of genotype frequencies between sporadic breast cancer patients and controls indicated the CT/TT-genotypes of +1506C>T and CG/CC-genotypes of +3204G>C were associated with decreased breast cancer risk (adjusted odds ratio (OR), 0.77; 95% confidence interval (CI), 0.62-0.96; and adjusted OR, 0.71; 95%CI, 0.57-0.88, respectively) compared with their wild-type homozygotes. A common hyplotype CGTCC was also associated with reduced risk (P=1.0×10-4). In a second familial breast cancer patient-based case-control study, although +1506C>T and +3204G>C failed to be validated, the haplotype CGTCC showed a borderline significance. Notably, the combined P-values were robust for +3204G>C (P=3.1×10-4) and CGTCC (P=1.6×10-5). Moreover, CGTCC was correlated with a higher GADD45A expression in normal breast tissues. In conclusion, although germline mutation of GADD45A is not common in familial breast cancer patients, polymorphisms/haplotypes in GADD45A contribute to breast cancer risk, at least to sporadic breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5163.