Liu Geoffrey, Wheatley-Price Paul, Zhou Wei, Park Sohee, Heist Rebecca S, Asomaning Kofi, Wain John C, Lynch Thomas J, Su Li, Christiani David C
Applied Molecular Oncology/Department of Medicine, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.
Int J Cancer. 2008 Feb 15;122(4):915-8. doi: 10.1002/ijc.23178.
Abnormalities of the tumor suppressor TP53 pathway are critical in the development of many cancers since it regulates cell cycle components and apoptosis. Murine double minute-2 (MDM2) protein is a central node in the p53 pathway and a direct negative regulator of p53. The MDM2 SNP309 (rs2279744) polymorphism increases MDM2 RNA and protein levels, attenuating the p53 pathway. The MDM2 SNP309 polymorphism was investigated in 1,787 Caucasian nonsmall cell lung cancer (NSCLC) patients and 1,360 healthy controls. Cases and controls were analyzed for associations with genotype and adjusted for age, gender, histology and smoking history. There were no overall associations between the MDM2 genotypes and risk of lung cancer (adjusted odds ratios [AORs] = 0.82 [95% confidence interval [CI] = 0.6-1.1] for the T/G genotype and AOR = 1.32 [95% CI = 0.9-2.0] for the G/G genotype). A statistically significant interaction (p = 0.01) was found between smoking and MDM2 genotypes. Consistent with this interaction, stratified analysis by pack-years of smoking demonstrated that the AORs of G/G vs. T/T were 1.56 (1.0-2.7), 1.46 (1.0-2.2), 0.80 (0.5-1.3) and 0.63 (0.4-1.1), respectively, for never, mild (<30 pack-years), moderate (30-57 pack-years) and heavy smokers (>or=58 pack-years). In conclusion, a strong gene-smoking interaction was observed between the MDM2 SNP309 and NSCLC risk.
肿瘤抑制因子TP53通路的异常在许多癌症的发生发展中至关重要，因为它调控细胞周期成分和细胞凋亡。小鼠双微体2（MDM2）蛋白是p53通路的核心节点，也是p53的直接负调控因子。MDM2 SNP309（rs2279744）多态性会增加MDM2 RNA和蛋白水平，减弱p53通路。对1787例白种人非小细胞肺癌（NSCLC）患者和1360例健康对照者进行了MDM2 SNP309多态性研究。分析病例和对照与基因型的关联，并对年龄、性别、组织学和吸烟史进行校正。MDM2基因型与肺癌风险之间无总体关联（T/G基因型的校正比值比[AORs]=0.82[95%置信区间[CI]=0.6 - 1.1]，G/G基因型的AOR = 1.32[95%CI = 0.9 - 2.0]）。发现吸烟与MDM2基因型之间存在统计学显著的相互作用（p = 0.01）。与这种相互作用一致，按吸烟包年数进行分层分析表明，从不吸烟、轻度（<30包年）、中度（30 - 57包年）和重度吸烟者（≥58包年）的G/G与T/T的AOR分别为1.56（1.0 - 2.7）、1.46（1.0 - 2.2）、0.80（0.5 - 1.3）和0.63（0.4 - 1.1）。总之，观察到MDM2 SNP309与NSCLC风险之间存在强烈的基因-吸烟相互作用。
