Sprague Brian L, Trentham-Dietz Amy, Garcia-Closas Montserrat, Newcomb Polly A, Titus-Ernstoff Linda, Hampton John M, Chanock Stephen J, Haines Jonathan L, Egan Kathleen M
Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI 53726, USA.
Carcinogenesis. 2007 Aug;28(8):1680-6. doi: 10.1093/carcin/bgm097. Epub 2007 Apr 21.
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 (1,490 cases/1,291 controls) breast cancer. Oral mucosal DNA samples were genotyped for the codon 72 polymorphism in exon 4 (rs1,042,522), 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, r(2) = 0.95) on intron 7 (rs12,951,053, rs12,947,788) 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 (rs9,894,946), and in two correlated SNPs (D' = 0.94, r(2) = 0.81) in introns 6 (rs1,625,895) and 4 (rs2,909,430), 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.
肿瘤抑制基因TP53的种系错义突变与乳腺癌的显著易感性相关，而单核苷酸多态性（SNP）在乳腺癌易感性中可能起的作用较小。在威斯康星州、马萨诸塞州和新罕布什尔州开展的一项基于人群的病例对照研究中，我们研究了20至74岁女性中TP53基因变异与乳腺癌风险的关系。分别对原位癌（176例病例/581例对照）和浸润性癌（1490例病例/1291例对照）进行分析。对口腔黏膜DNA样本进行基因分型，检测第4外显子（rs1042522）的密码子72多态性、7个内含子SNP以及位于3'非翻译区（UTR）的3个SNP。采用逻辑回归分析得出各SNP经年龄和州别校正后的比值比。使用PHASE软件重建单倍型，并通过全局评分检验评估与乳腺癌风险的总体关联。11个单个SNP或8个常见单倍型均与原位乳腺癌风险无显著相关性。在所有女性中，内含子7上的两个连锁SNP（D' = 0.99，r(2) = 0.95，rs12951053、rs12947788）与浸润性乳腺癌风险的适度增加相关；然而，仅杂合子携带者的关联具有统计学意义。数据表明，3'UTR中的其他变异（rs9894946）以及内含子6（rs1625895）和内含子4（rs2909430）中的两个相关SNP（D' = 0.94，r(2) = 0.81）仅与50岁及以下女性浸润性乳腺癌风险降低相关（交互作用P < 0.03）。这些结果表明，TP53基因的常见变异可能会改变浸润性乳腺癌的风险。
