Gaudet Mia M, Gammon Marilie D, Bensen Jeannette T, Sagiv Sharon K, Shantakumar Sumitra, Teitelbaum Susan L, Eng Sybil M, Neugut Alfred I, Santella Regina M
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA,
Breast Cancer Res Treat. 2008 Mar;108(1):93-9. doi: 10.1007/s10549-007-9573-0. Epub 2007 Jul 12.
p53 participates in cell cycle control, programmed cell death/apoptosis, and DNA repair, all pathways involved in carcinogenesis. TP53 variants may influence p53 function.
We evaluated whether three well-characterized TP53 variants -- Ex4 + 119 C > G (rs#1042522, Arg72Pro), IVS6 + 62 A > G (rs#1625895), and an IVS3 16 bp insertion/ deletion (INDEL; rs#17878362) -- were associated with breast cancer risk in a population-based case-control study.
Genotypes and haplotypes were determined using long-range PCR in a sample of 578 cases and 390 controls.
For the Ex4 + 19 C > G SNP (rs1042522), women with the heterozygous genotype (G/C) had a 32% increase in breast cancer risk. Other variants were not associated with risk. We further examined whether these associations were modified by cigarette smoking status and detection of PAH-DNA adducts in circulating lymphocytes. Among current smokers, each copy of the minor alleles for the IVS6 + 62 A > G SNP (rs1625895) and the IVS3 INDEL polymorphism (rs17878362) was associated with lower breast cancer risk (OR = 0.49, 95% CI 0.27-0.90; OR = 0.42, 95% CI 0.22-0.78, respectively). However, among former smokers, the homozygous variant genotype for these 2 SNPs was observed among cases (4.1 and 3.2%, respectively) and not controls. Genotype associations were not modified by the presence or absence of DNA adducts in circulating lymphocytes. Three-loci haplotypes were not significantly associated with breast cancer risk.
These results should be confirmed in larger studies, but suggest that cigarette smoking may influence breast cancer risk through interaction with p53.
p53参与细胞周期调控、程序性细胞死亡/凋亡以及DNA修复，这些都是与癌症发生相关的途径。TP53变异可能会影响p53功能。
在一项基于人群的病例对照研究中，我们评估了三个特征明确的TP53变异——Ex4 + 119 C > G（rs#1042522，Arg72Pro）、IVS6 + 62 A > G（rs#1625895）以及IVS3 16 bp插入/缺失（INDEL；rs#17878362）——是否与乳腺癌风险相关。
在578例病例和390例对照的样本中，使用长程PCR确定基因型和单倍型。
对于Ex4 + 19 C > G单核苷酸多态性（SNP，rs1042522），杂合基因型（G/C）的女性患乳腺癌风险增加32%。其他变异与风险无关。我们进一步研究了吸烟状态和循环淋巴细胞中多环芳烃-DNA加合物的检测是否会改变这些关联。在当前吸烟者中，IVS6 + 62 A > G SNP（rs1625895）和IVS3 INDEL多态性（rs17878362）的每个次要等位基因拷贝都与较低的乳腺癌风险相关（OR = 0.49，95%CI 0.27 - 0.90；OR = 0.42，95%CI 0.22 - 0.78）。然而，在既往吸烟者中，病例中观察到这两个SNP的纯合变异基因型（分别为4.1%和3.2%），而对照中未观察到。循环淋巴细胞中DNA加合物的存在与否并未改变基因型关联。三位点单倍型与乳腺癌风险无显著关联。
这些结果应在更大规模的研究中得到证实，但表明吸烟可能通过与p53相互作用影响乳腺癌风险。
