Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Surgery. 2013 May;153(5):711-7. doi: 10.1016/j.surg.2012.11.009. Epub 2012 Dec 4.
Murine double minute 2 (MDM2) oncoprotein and p14(ARF) tumor suppressor play pivotal roles in regulating p53 and function in the MAPK pathway, which is mutated frequently in differentiated thyroid carcinoma (DTC). We hypothesized that functional polymorphisms in the promoters of MDM2 and p14(ARF) contribute to the interindividual difference in predisposition to DTC.
MDM2-rs2279744, MDM2-rs937283, p14(ARF)-rs3731217, and p14(ARF)-rs3088440 were genotyped in 303 patients with DTC and 511 cancer-free healthy controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
MDM2-rs2279744 and p14(ARF)-rs3731217 were associated with a significantly increased risk of DTC (MDM2-rs2279744: TT versus TG/GG; OR, 1.5; 95% CI, 1.1-2.0; p14(ARF)-rs3731217: TG/GG versus TT; OR, 1.7; 95% CI, 1.2-2.3). No association was found for MDM2-rs937283 or p14(ARF)-rs3088440. Individuals carrying 3-4 risk genotypes of MDM2 and p14(ARF) had 2.2 times (95% CI, 1.4-3.5) the risk for DTC of individuals carrying 0-1 risk genotypes (P trend = .021). The combined effect of MDM2 and p14(ARF) on risk of DTC was confined to young subjects (≤ 45 years), nonsmokers, nondrinkers, and subjects with a first-degree family history of cancer. These associations were quite similar in strength when cases were restricted to those with papillary thyroid cancer.
Our results suggest that polymorphisms of MDM2 and p14(ARF) contribute to the interindividual difference in susceptibility to DTC, either alone or more likely jointly. The observed associations warrant further confirmation in independent studies.
鼠双微体 2 基因（MDM2）癌蛋白和 p14（ARF）肿瘤抑制因子在调节 p53 方面发挥着关键作用，并作用于 MAPK 通路，该通路在分化型甲状腺癌（DTC）中经常发生突变。我们假设 MDM2 和 p14（ARF）启动子中的功能多态性导致 DTC 易感性的个体间差异。
在 303 例 DTC 患者和 511 例无癌症的健康对照中，对 MDM2-rs2279744、MDM2-rs937283、p14（ARF）-rs3731217 和 p14（ARF）-rs3088440 进行了基因分型。采用多变量逻辑回归分析计算比值比（OR）和 95%置信区间（CI）。
MDM2-rs2279744 和 p14（ARF）-rs3731217 与 DTC 的发病风险显著增加相关（MDM2-rs2279744：TT 与 TG/GG；OR，1.5；95%CI，1.1-2.0；p14（ARF）-rs3731217：TG/GG 与 TT；OR，1.7；95%CI，1.2-2.3）。未发现 MDM2-rs937283 或 p14（ARF）-rs3088440 与风险相关。携带 MDM2 和 p14（ARF）3-4 种风险基因型的个体患 DTC 的风险是携带 0-1 种风险基因型个体的 2.2 倍（95%CI，1.4-3.5；P 趋势=0.021）。MDM2 和 p14（ARF）对 DTC 风险的联合作用仅限于年轻受试者（≤45 岁）、不吸烟者、不饮酒者以及有一级癌症家族史的个体。当病例仅限于甲状腺乳头状癌时，这些关联的强度相当相似。
我们的研究结果表明，MDM2 和 p14（ARF）的多态性单独或更可能共同导致 DTC 易感性的个体间差异。观察到的关联需要在独立研究中进一步证实。
