Talseth Bente A, Meldrum Cliff, Suchy Janina, Kurzawski Grzegroz, Lubinski Jan, Scott Rodney J
Discipline of Medical Genetics, Faculty of Health, University of Newcastle, and the Hunter Medical Research Institute, NSW Australia.
Int J Cancer. 2007 Feb 1;120(3):563-5. doi: 10.1002/ijc.22339.
Disease expression in hereditary nonpolyposis colorectal cancer (HNPCC) cannot be readily explained by mutation site in the respective DNA mismatch repair genes associated with this disorder. One explanation is the role of modifying genes that can either promote or prevent disease development on a background of increased risk. Two single nucleotide polymorphisms in MDM2 and TP53 have been shown to be associated with younger ages of disease onset in HNPCC (TP53) and Li-Fraumeni syndrome (MDM2). In this study 220 HNPCC patients were examined, from Australia and Poland, all characterized at the molecular level to determine the frequency of the MDM2 SNP309 T>G and to assess its influence on disease expression. The results were then pooled with the results of a previous study to assess the combined influence of the MDM2 SNP309 T>G and TP53 SNP R72P. A significant difference was observed between CRC patients and unaffected MMR gene mutation carriers over the age of 45 years (p = 0.01). The unaffected MMR gene mutation carriers over the age of 45 years who carry the G allele have a reduced risk of developing CRC. The results indicate that the MDM2 SNP309, alone or in combination with TP53 R72P, does not influence age of diagnosis of CRC in individuals with HNPCC. In conclusion, the data indicates the G allele of MDM2 SNP309 might have a protective effect on disease development in HNPCC patients and that age of diagnosis of CRC is not associated with MDM2 SNP309 or TP53 R72P either as single SNPs or combined.
遗传性非息肉病性结直肠癌（HNPCC）中的疾病表现不能简单地通过与该疾病相关的各个DNA错配修复基因中的突变位点来解释。一种解释是修饰基因的作用，即在风险增加的背景下，修饰基因可以促进或预防疾病的发展。MDM2和TP53中的两个单核苷酸多态性已被证明与HNPCC（TP53）和李-弗劳梅尼综合征（MDM2）中疾病发病年龄较轻有关。在本研究中，对来自澳大利亚和波兰的220例HNPCC患者进行了检查，所有患者均在分子水平进行了特征分析，以确定MDM2 SNP309 T>G的频率，并评估其对疾病表现的影响。然后将结果与先前一项研究的结果合并，以评估MDM2 SNP309 T>G和TP53 SNP R72P的联合影响。在45岁以上的结直肠癌患者和未受影响的错配修复基因突变携带者之间观察到显著差异（p = 0.01）。45岁以上携带G等位基因的未受影响的错配修复基因突变携带者患结直肠癌的风险降低。结果表明，MDM2 SNP309单独或与TP53 R72P联合使用，均不影响HNPCC患者结直肠癌的诊断年龄。总之，数据表明MDM2 SNP309的G等位基因可能对HNPCC患者的疾病发展具有保护作用，并且结直肠癌的诊断年龄与MDM2 SNP309或TP53 R72P均无关，无论是单个SNP还是联合使用。
