International Agency for Research on Cancer, Group of Molecular Carcinogenesis, Lyon, France.
Curr Opin Oncol. 2010 Jan;22(1):64-9. doi: 10.1097/CCO.0b013e328333bf00.
Germline TP53 (tumor protein 53) mutations are the molecular basis of a complex cancer predisposition syndrome, the Li-Fraumeni syndrome. The present review discusses the diversity of tumor patterns in TP53 mutation carriers, focusing on molecular factors that may explain familial and individual differences, such as genotype/phenotype correlations, genetic modifiers and genetic anticipation.
Initially identified 20 years ago, germline TP53 mutations appear to be associated with an extremely diverse range of cancers. Although no other gene has been found in Li-Fraumeni syndrome, recent results show that the functional effects of particular mutations, polymorphisms in TP53 or in regulators such as MDM2 (murine double minute 2), variations in DNA copy number and variations in telomere length, have a strong impact on individual risk and on tumor patterns. Furthermore, recent studies in large cohorts suggest that TP53 germline mutations may occur in up to 1: 5000 individuals.
Germline TP53 mutations may be responsible for a large fraction (15-20%) of all inherited cancers. Although mutations are detectable by sequencing, counseling and follow-up remain problematic due to the wide variations in disease presentation. Elucidating the molecular mechanisms underlying the predisposition caused by TP53 deficiency may help to develop better, evidence-based and personalized clinical protocols.
胚系 TP53（肿瘤蛋白 53）突变是一种复杂的癌症易感性综合征——李-佛美尼综合征的分子基础。本综述讨论了 TP53 突变携带者中肿瘤模式的多样性，重点讨论了可能解释家族和个体差异的分子因素，如基因型/表型相关性、遗传修饰因子和遗传预期。
胚系 TP53 突变最初在 20 年前被发现，似乎与极其多样化的癌症有关。虽然在李-佛美尼综合征中尚未发现其他基因，但最近的结果表明，特定突变、TP53 中的多态性或调节剂（如 MDM2（双微鼠基因 2））、DNA 拷贝数的变化和端粒长度的变化等的功能效应对个体风险和肿瘤模式有很强的影响。此外，在大型队列中的最近研究表明，TP53 胚系突变可能发生在多达 1:5000 的个体中。
胚系 TP53 突变可能导致所有遗传性癌症的很大一部分（15-20%）。尽管可以通过测序检测到突变，但由于疾病表现的广泛变化，咨询和随访仍然存在问题。阐明由 TP53 缺陷引起的易感性的分子机制可能有助于制定更好的、基于证据的和个性化的临床方案。
