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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene
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Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

机译：人类MDM4癌基因中肿瘤形成的改变和遗传变异的进化选择

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摘要

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nuclectide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pi assure (1-4). In this report, we analyze the haplotype structure of MIDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.
机译：大量证据强烈表明，p53抑癌途径是降低脊椎动物癌症发生率的关键。单倍剂量不足的小鼠双分钟2（MDM2）癌基因的蛋白质产物结合并抑制p53蛋白。对p53和MDM2中人类遗传变异的最新研究表明，单个核苷多态性（SNP）可以影响p53信号传导，赋予癌症风险，并表明该途径处于进化选择性pisure之下（1-4）。在本报告中，我们分析了几种不同人群中MIDM4（MDM2的结构同源物）的单倍型结构。 MDM4的单倍型分布中连锁不平衡（LD）的异常模式表明存在候选SNP，也可能修饰p53途径的功效。在5个不同患者人群中的关联研究表明，MDM4中的这些SNP分别使Ashkenazi犹太人和欧洲人的人群乳腺癌和卵巢癌的风险增加或早发。该报告不仅暗示MDM4是人类乳腺和卵巢肿瘤发生的关键调节因子，而且还首次利用进化驱动的连锁不平衡作为选择可能与临床相关的p53途径基因的SNP的手段。

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