Sinilnikova O M, Antoniou A C, Simard J, Healey S, Léoné M, Sinnett D, Spurdle A B, Beesley J, Chen X, Greene M H, Loud J T, Lejbkowicz F, Rennert G, Dishon S, Andrulis I L, Domchek S M, Nathanson K L, Manoukian S, Radice P, Konstantopoulou I, Blanco I, Laborde A L, Durán M, Osorio A, Benitez J, Hamann U, Hogervorst F B L, van Os T A M, Gille H J P, Peock S, Cook M, Luccarini C, Evans D G, Lalloo F, Eeles R, Pichert G, Davidson R, Cole T, Cook J, Paterson J, Brewer C, Hughes D J, Coupier I, Giraud S, Coulet F, Colas C, Soubrier F, Rouleau E, Bièche I, Lidereau R, Demange L, Nogues C, Lynch H T, Schmutzler R K, Versmold B, Engel C, Meindl A, Arnold N, Sutter C, Deissler H, Schaefer D, Froster U G, Aittomäki K, Nevanlinna H, McGuffog L, Easton D F, Chenevix-Trench G, Stoppa-Lyonnet D
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon, Centre Léon Bérard, Lyon 69373, France.
Br J Cancer. 2009 Oct 20;101(8):1456-60. doi: 10.1038/sj.bjc.6605279. Epub 2009 Aug 25.
The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.
To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.
No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.
There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.
TP53通路以TP53及其负调节因子MDM2为核心元件，在致癌过程中发挥重要作用，尤其是在BRCA1和BRCA2介导的致癌过程中。MDM2启动子区域的单核苷酸多态性（SNP）（309T>G，rs2279744）和TP53的编码SNP（Arg72Pro，rs1042522）已被证明具有功能意义。
为了研究这些SNP是否会改变BRCA1和BRCA2突变携带者患乳腺癌的风险，我们汇总了来自BRCA1/2修饰因子研究联盟（CIMBA）的7011名突变携带者中TP53 Arg72Pro SNP的基因型数据以及2222名突变携带者中MDM2 309T>G SNP的基因型数据。在回顾性似然框架内使用Cox比例风险模型对数据进行分析。
未发现这些SNP与BRCA1突变携带者患乳腺癌的风险之间存在关联（TP53：等位基因风险比（HR）=1.01，95%置信区间（CI）：0.93 - 1.10，P（趋势）=0.77；MDM2：HR=0.96，95%CI：0.84 - 1.09，P（趋势）=0.54），也未发现与BRCA2突变携带者患乳腺癌的风险之间存在关联（TP53：HR=0.99，95%CI：0.87 - 1.12，P（趋势）=0.83；MDM2：HR=0.98，95%CI：0.80 - 1.21，P（趋势）=0.88）。我们还评估了这两个SNP对乳腺癌风险的潜在联合效应，然而，它们的任何联合基因型均未显示出关联的证据。
没有证据表明TP53 Arg72Pro或MDM2 309T>G单独或联合起来会影响BRCA1或BRCA2突变携带者患乳腺癌的风险。
