Effects of MDM2, MDM4 and TP53 Codon 72 Polymorphisms on Cancer Risk in a Cohort Study of Carriers of TP53 Germline Mutations
Effects of MDM2, MDM4 and TP53 Codon 72 Polymorphisms on Cancer Risk in a Cohort Study of Carriers of TP53 Germline Mutations
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DOI：
10.1371/journal.pone.0010813
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发表时间：
2010-05-26
期刊：
影响因子：
3.7
通讯作者：
Amos, Christopher I.
中科院分区：
文献类型：
--
作者：
Fang, Shenying;Krahe, Ralf;Amos, Christopher I.
背景：以往的研究表明，MDM2 SNP309和p53密码子72对种系p53突变具有修饰作用，但这些研究仅依赖于小样本量的病例研究。MDM4多态性对种系突变携带者肿瘤发病的影响此前尚未被研究。方法/主要发现：我们分析了213名p53种系突变携带者，其中168名（78.9%）患有癌症，174名有基因型数据。我们采用Kaplan-Meier和Cox比例风险法分析首次发生癌症的时间，根据多态性基因型比较风险。对于MDM2 SNP309， GG/GT和TT携带者的平均癌症诊断年龄差异为9.0岁（18.6岁对27.6岁，P = 0.0087）。GG/GT个体的风险与TT个体的风险比为1.58 (P = 0.03)，但这种影响仅在女性中显著（HR = 1.60, P = 0.02）。与其他基因型相比，P53密码子72pp纯合子的癌症发生时间比其他基因型高2.24倍（P = 0.03）。我们观察到MDM2和p53密码子72多态性对风险的倍增联合效应。MDM4多态性无显著影响。结论/意义：我们的研究结果表明，MDM2 SNP309 G等位基因与p53种系突变携带者的癌症风险相关，并在女性中显著加速癌症发病时间。MDM2 SNP309 G等位基因与p53密码子72g等位基因之间存在乘法联合效应，与癌症发生风险相关。我们的研究结果进一步确定了生殖系p53突变携带者的癌症风险。
Background: Previous studies have shown that MDM2 SNP309 and p53 codon 72 have modifier effects on germline P53 mutations, but those studies relied on case-only studies with small sample sizes. The impact of MDM4 polymorphism on tumor onset in germline mutation carriers has not previously been studied.Methodology/Principal Findings: We analyzed 213 p53 germline mutation carriers including 168(78.9%) affected with cancer and 174 who had genotypic data. We analyzed time to first cancer using Kaplan-Meier and Cox proportional hazards methods, comparing risks according to polymorphism genotypes. For MDM2 SNP309, a significant difference of 9.0 years in the average age of cancer diagnosis was observed between GG/GT and TT carriers (18.6 versus 27.6 years, P = 0.0087). The hazards ratio was 1.58 (P = 0.03) comparing risks among individuals with GG/GT to risk among TT, but this effect was only significant in females (HR = 1.60, P = 0.02). Compared to other genotypes, P53 codon 72 PP homozygotes had a 2.24 times (P = 0.03) higher rate for time to develop cancer. We observed a multiplicative joint effect of MDM2 and p53 codon72 polymorphism on risk. The MDM4 polymorphism had no significant effects.Conclusions/Significance: Our results suggest that the MDM2 SNP309 G allele is associated with cancer risk in p53 germline mutation carriers and accelerates time to cancer onset with a pronounced effect in females. A multiplicative joint effect exists between the MDM2 SNP309 G allele and the p53 codon 72 G allele in the risk of cancer development. Our results further define cancer risk in carriers of germline p53 mutations.