文章：

P53多态性：癌症意义

p53 polymorphisms: cancer implications

原文发布日期：2009-02-01

DOI: 10.1038/nrc2584

类型: Review Article

开放获取: 否

要点：

1. TP53, which encodes p53, is a tumour suppressor gene that is frequently mutated in sporadic cancers. The mutations are usually single base substitutions that disrupt function, and some confer new oncogenic (gain-of-function) properties. Over 200 single nucleotide polymorphisms (SNPs; germline variants) in TP53 have been identified; in contrast to tumour-associated mutations, most of these TP53 SNPs are unlikely to have biological effects. Owing to the importance of p53 in tumour suppression, the polymorphisms that alter p53 function might affect cancer risk, progression and/or response to treatment.
2. p53 lies at the hub of a vast signalling network. Polymorphisms in upstream activators, repressors or downstream effectors of p53 might individually modulate cancer risk or interact with polymorphisms or mutations in TP53.
3. Because the effects of a polymorphism can be subtle and can vary according to genetic background, there are rigorous methodological challenges associated with determining the effect of a polymorphism on cancer risk. Even for the most studied SNP in p53 at codon 72, R72P, the results have been inconsistent, particularly those from population studies that have investigated associations with cancer risk.
4. Population studies require large sample sizes (in the thousands). High-throughput sequencing and the development of genome-wide SNP maps are allowing larger and more comprehensive studies of polymorphisms to be carried out. To date, no study of a sufficient size has reported a significant association between SNPs at the TP53 locus and altered cancer risk.
5. Molecular studies examining the effects of p53 polymorphisms have been based principally on in vitro models with transfected cell lines. The biological effects of p53 pathway variants at the molecular level in primary cells or in vivo still need to be determined. The design of genetically engineered mice using knock-in and knockout technology to study human polymorphisms is currently underway.

要点翻译：

1. TP53基因编码p53蛋白，是一种在散发性癌症中频繁发生突变的抑癌基因。这些突变通常为破坏其功能的单碱基替换，其中部分突变还会赋予新的致癌特性（功能获得性突变）。目前已在TP53基因中发现200多种单核苷酸多态性（SNPs；种系变异），与肿瘤相关突变不同，大多数TP53单核苷酸多态性不太可能产生生物学效应。由于p53在肿瘤抑制中的重要性，那些改变p53功能的多态性可能会影响癌症风险、进展和/或治疗反应。
2. p53处于庞大信号网络的枢纽位置。其上游激活因子、抑制因子或下游效应因子中的多态性可能单独调节癌症风险，或与TP53基因的多态性或突变产生相互作用。
3. 由于多态性的影响可能十分微妙且随遗传背景变化而不同，确定多态性对癌症风险的影响面临着严格的方法学挑战。即使对于研究最深入的p53密码子72多态性（R72P），不同研究结果仍存在矛盾，特别是在探究与癌症风险关联的人群研究中尤为明显。
4. 人群研究需要大样本量（数千例）。高通量测序和全基因组SNP图谱的发展使得更大规模、更全面的多态性研究成为可能。迄今为止，尚未有足够规模的研究报道TP53位点SNP与癌症风险改变存在显著关联。
5. 针对p53多态性效应的分子研究主要基于转染细胞系的体外模型。p53通路变异在原始细胞或体内分子水平的生物学效应仍有待确定。目前正在利用基因敲入和敲除技术设计基因工程小鼠模型，用以研究人类基因多态性。

英文摘要：

The normal functioning of p53 is a potent barrier to cancer. Tumour-associated mutations in TP53, typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 function. By contrast, only a small fraction, if any, of the >200 naturally occurring sequence variations (single nucleotide polymorphisms, SNPs) of TP53 in human populations are expected to cause measurable perturbation of p53 function. Polymorphisms in the TP53 locus that might have cancer-related phenotypical manifestations are the subject of this Review. Polymorphic variants of other genes in the p53 pathway, such as MDM2, which might have biological consequences either individually or in combination with p53 variants are also discussed.

摘要翻译： 

p53的正常功能是癌症的强大屏障。TP53中与肿瘤相关的突变（通常是编码序列中的单核苷酸替换）是大多数人类癌症的标志，并导致p53功能出现严重缺陷。相比之下，人类群体中TP53的200多种自然发生的序列变异（单核苷酸多态性，SNP）中，只有一小部分（如果有的话）预计会对p53功能产生可测量的扰动。本综述的主题是TP53基因座中可能与癌症相关表型表现的多态性。还讨论了p53通路中其他基因（如MDM2）的多态性变异，这些变异可能单独或与p53变异联合产生生物学后果。

原文链接：

p53 polymorphisms: cancer implications