Rose Stephen L, Robertson Andrew D, Goodheart Michael J, Smith Brian J, DeYoung Barry R, Buller Richard E
The Holden Comprehensive Cancer Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
Clin Cancer Res. 2003 Sep 15;9(11):4139-44.
Although survival with a p53 missense mutation is highly variable, p53-null mutation is an independent adverse prognostic factor for advanced stage ovarian cancer. By evaluating ovarian cancer survival based upon a structure function analysis of the p53 protein, we tested the hypothesis that not all missense mutations are equivalent.
The p53 gene was sequenced from 267 consecutive ovarian cancers. The effect of individual missense mutations on p53 structure was analyzed using the International Agency for Research on Cancer p53 Mutational Database, which specifies the effects of p53 mutations on p53 core domain structure. Mutations in the p53 core domain were classified as either explained or not explained in structural or functional terms by their predicted effects on protein folding, protein-DNA contacts, or mutation in highly conserved residues. Null mutations were classified by their mechanism of origin.
Mutations were sequenced from 125 tumors. Effects of 62 of the 82 missense mutations (76%) could be explained by alterations in the p53 protein. Twenty-three (28%) of the explained mutations occurred in highly conserved regions of the p53 core protein. Twenty-two nonsense point mutations and 21 frameshift null mutations were sequenced. Survival was independent of missense mutation type and mechanism of null mutation.
The hypothesis that not all missense mutations are equivalent is, therefore, rejected. Furthermore, p53 core domain structural alteration secondary to missense point mutation is not functionally equivalent to a p53-null mutation. The poor prognosis associated with p53-null mutation is independent of the mutation mechanism.
尽管携带p53错义突变的患者生存率差异很大，但p53基因缺失突变是晚期卵巢癌独立的不良预后因素。通过基于p53蛋白结构功能分析评估卵巢癌生存率，我们检验了并非所有错义突变都等效的假说。
对267例连续的卵巢癌进行p53基因测序。使用国际癌症研究机构的p53突变数据库分析单个错义突变对p53结构的影响，该数据库明确了p53突变对p53核心结构域结构的影响。根据对蛋白质折叠、蛋白质-DNA相互作用或高度保守残基突变的预测效应，将p53核心结构域中的突变按其对结构或功能的影响分为可解释或不可解释两类。基因缺失突变按其起源机制分类。
对125例肿瘤进行了测序。82个错义突变中的62个（76%）的影响可通过p53蛋白的改变来解释。23个（28%）可解释的突变发生在p53核心蛋白的高度保守区域。对22个无义点突变和21个移码缺失突变进行了测序。生存率与错义突变类型和缺失突变机制无关。
因此，并非所有错义突变都等效的假说被否定。此外，错义点突变继发的p53核心结构域结构改变在功能上不等同于p53基因缺失突变。与p53基因缺失突变相关的不良预后与突变机制无关。
