Common genetic variation in TP53 and its flanking genes, WDR79 and ATP1B2, and susceptibility to breast cancer

Abstract

Germline mutations in the tumor suppressor gene TP53 are associated with high incidence of early-onset malignancies, and somatic mutations occur in 20-40% of all breast cancer cases. We investigated the association of common genetic variation in TP53 and its flanking genes, WDR79 and ATP1B2, with risk for breast cancer. Single nucleotide polymorphisms (SNPs) identified in a re-sequence analysis were genotyped in 2 large case-control studies including 731 cases and 1,124 controls from Norway, and 1,995 cases and 2,296 controls from Poland. Analyses of the pooled data showed no SNPs in TP53 to be significantly associated with risk for breast cancer. However, we found a significant and consistent association with risk for a SNP in exon 1 (R68G) of the 5' neighboring gene WDR79 (rs2287499, OR (95% CI) = 1.08 (0.95-1.23) for CG vs. CC and 1.60 (1.04-2.47) for GG vs. CC, p-trend = 0.01). Stratification by ER and PR status, showed these increases in risk to be limited to ER negative tumors (OR (95% CI) per variant allele: 1.42 (1.18-1.71) p-trend = 0.00009). In addition, 2 TP53 SNPs (rs17887200 3'of STP and rs12951053 in intron 7) showing weak and non-significant overall increases in risk, were also associated with ER negative tumors (1.48 (1.11-1.93) p-trend = 0.01 and 1.29 (1.06-1.58) p-trend = 0.009, respectively). In conclusion, this comprehensive evaluation of common genetic variation in TP53 and its flanking genes found no significant overall associations between SNPs in TP53 and breast cancer risk. However, data suggested that common variation in TP53 or WDR79 could be associated with ER negative breast cancers.