Genetic variation in TP53 and risk of breast cancer in a population-based case-control study

Whereas germ line missense mutations in the tumor suppressor gene TP53 are associated with a marked predisposition to breast cancer, single-nucleotide polymorphisms (SNPs) may play a more modest role in breast cancer susceptibility. We examined genetic variation in TP53 in relation to breast cancer risk among women aged 20-74 years in a population-based case-control study in Wisconsin, Massachusetts and New Hampshire. Analyses were conducted separately for in situ (176 cases/581 controls) and invasive (1490 cases/1291 controls) breast cancer. Oral mucosal DNA samples were genotyped for the codon 72 polymorphism in exon 4 (rs1042522), seven intronic SNPs and three SNPs residing in the 3′ untranslated region (UTR). Logistic regression was used to obtain age- and state-adjusted odds ratios for individual SNPs. Haplotypes were reconstructed using PHASE software, and the overall association with breast cancer risk was assessed using a global score test. None of the 11 individual SNPs or eight common haplotypes were significantly related to breast carcinoma in situ risk. Among all women, two linked SNPs (D′ = 0.99, r² = 0.95) on intron 7 (rs12951053, rs12947788) were associated with modest increases in invasive breast cancer risk; however, associations were only significant for heterozygous carriers. The data suggested that additional variants in the 3′ UTR (rs9894946), and in two correlated SNPs (D′ = 0.94, r² = 0.81) in introns 6 (rs1625895) and 4 (rs2909430), were associated with reduced invasive breast cancer risk among women aged 50 and younger only (P_interaction <0.03). These results indicate that common variation in the TP53 gene could modify the risk of invasive breast cancer.