p53 Arg72Pro polymorphism, adiposity status, and cancer risk: Two case‐cohorts within a Japanese prospective study

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/m(2) (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/m(2). 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.