The tumor suppressor protein, p53, is a critical molecule involved in cancer development. However, the association between p53 Arg72Pro polymorphism and cancer risk remains unclear, possibly due to the pro-tumor potential of p53 under metabolic stress. Here, we hypothesized that the p53 Arg72Pro polymorphism plays different roles during tumorigenesis by adiposity status. We measured baseline body mass index (BMI) and p53 Arg72Pro polymorphism for two case-cohorts, which included 4264 cancers with up to 20 years of follow-up. Multivariable-adjusted hazard ratios (HRs) and confidence intervals (CIs) were estimated using weighted Cox proportional-hazards method. Without consideration of adiposity status, p53 Arg72Pro polymorphism was not associated with cancer risk. However, proline (Pro) homozygous genotype conferred an increased cancer risk for individuals with a BMI <25 kg/m² (HR [95% CI]: 1.12 [1.00–1.26] for total cancer and 1.19 [1.02–1.38] for obesity-related cancer), but not for those with a BMI ≥ 25 kg/m². The heterogeneous effect of p53 Arg72Pro polymorphism on cancer risk according to adiposity status was indicated (p_{heterogeneity}: 0.07 for total cancer and 0.03 for obesity-related cancer). Furthermore, the association between overweight and cancer risk was only observed in arginine (Arg) carriers, but not in Pro homozygous carriers (p_{heterogeneity}: 0.07 for total cancer and 0.02 for obesity-related cancer). Pro homozygous carriers were more likely to be predisposed to cancer than Arg carriers with normal-weight conditions. In addition, overweight was related to a higher cancer risk in Arg carriers than Pro homozygous carriers. Our findings may suggest the adiposity-dependent dual effects of p53 Arg72Pro polymorphism during tumorigenesis.

中文翻译：

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p53 Arg72Pro 多态性、肥胖状态和癌症风险：日本前瞻性研究中的两个病例队列

肿瘤抑制蛋白 p53 是参与癌症发展的关键分子。然而，p53 Arg72Pro 多态性与癌症风险之间的关联仍不清楚，这可能是由于 p53 在代谢应激下的促肿瘤潜力。在这里，我们假设 p53 Arg72Pro 多态性在不同肥胖状态的肿瘤发生过程中发挥不同的作用。我们测量了两个病例队列的基线体重指数 (BMI) 和 p53 Arg72Pro 多态性，其中包括 4264 例癌症，随访时间长达 20 年。使用加权 Cox 比例风险方法估计多变量调整后的风险比 (HR) 和置信区间 (CI)。在不考虑肥胖状况的情况下，p53 Arg72Pro 多态性与癌症风险无关。然而，²（HR [95% CI]：总癌症为 1.12 [1.00–1.26]，肥胖相关癌症为 1.19 [1.02–1.38]），但 BMI ≥ 25 kg/m ²的患者则不然。根据肥胖状况，p53 Arg72Pro 多态性对癌症风险的异质性影响被指出（p_异质性：总癌症为 0.07，肥胖相关癌症为 0.03）。此外，仅在精氨酸 (Arg) 携带者中观察到超重与癌症风险之间的关联，但在 Pro 纯合子携带者中未观察到（p_异质性：总癌症为 0.07，肥胖相关癌症为 0.02）。与体重正常的 Arg 携带者相比，Pro 纯合子携带者更容易患癌症。此外，超重与 Arg 携带者的癌症风险高于 Pro 纯合子携带者有关。我们的研究结果可能表明 p53 Arg72Pro 多态性在肿瘤发生过程中的肥胖依赖性双重效应。