The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1
The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1
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DOI：
10.1016/j.canlet.2006.12.006
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发表时间：
2007-07-08
期刊：
影响因子：
9.7
通讯作者：
Schackert, Hans K.
中科院分区：
文献类型：
--
作者：
Krueger, Stefan;Engel, Christoph;Schackert, Hans K.
p53 和前列腺癌易感基因 RNASEL 是参与细胞凋亡的肿瘤抑制基因。我们之前报道过，p53 中常见的、功能不同的 Arg72Pro 和 RNASEL 中的 Arg462Gln 与林奇综合征患者结直肠癌的发病年龄相关。为了评估两种变异的综合效应，我们筛查了 246 名不相关的林奇综合征患者，这些患者在 MSH2 (n = 138) 或 MLH1 (n = 108) 中存在致病性种系突变，并且结直肠癌作为第一个肿瘤，以及 245 名健康对照。全局对数等级检验显示，每种变异的基因型（p53 的 p = 0.0176，RNASEL 的 p = 0.0358）和两种变异的组合基因型（p = 0.0174）的发病年龄存在显着差异。两个基因的野生型纯合子（42岁[范围22-75]）和两个基因的变异等位基因纯合子（30岁[范围26-47]）之间的中位发病年龄差异最大。多变量 Cox 回归模型表明，在加性遗传模式中，只有 p53 和 RNASEL 基因型对发病年龄有显着影响（p53 的 p = 0.016，RNASEL 的 p = 0.014），并且两种变异的影响纯粹是加性的，这支持了 p53 和 RNaseL 途径不相互作用的观点。这些发现可能与林奇综合征的预防策略相关。 (c) 2006 Elsevier Ireland Ltd. 保留所有权利。
p53 and the prostate-cancer-susceptibility gene RNASEL are tumour suppressor genes involved in apoptosis. We have previously reported that the common, functionally different variants Arg72Pro in p53 and Arg462Gln in RNASEL are associated with the age of disease onset of colorectal cancer in Lynch syndrome patients. To assess the combined effect of both variants, we screened 246 unrelated Lynch syndrome patients with a pathogenic germline mutation either in MSH2 (n = 138) or in MLH1 (n = 108) and colorectal cancer as first tumour, and 245 healthy controls. The global log rank test revealed significant differences in the age of disease onset for the genotypes of each variant (p = 0.0176 for p53 and p = 0.0358 for RNASEL) and for the combined genotypes of both variants (p = 0.0174). The highest difference in median age of disease onset was seen between homozygotes for the wild-types in both genes (42 years [range 22-75]) and homozygotes for the variant alleles in both genes (30 years [range 26-47]). A multivariate Cox regression model indicated that only the p53 and RNASEL genotypes had a significant influence on age of disease onset (p = 0.016 for p53 and p = 0.014 for RNASEL) in an additive mode of inheritance, and that the effects of both variants are purely additive, which supports the notion that the p53 and RNaseL pathways do not interact. These findings may be relevant for preventive strategies in Lynch syndrome. (c) 2006 Elsevier Ireland Ltd. All rights reserved.