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Background: Gastrointestinal (GI) cancer risk has been associated with metabolic syndrome (MetS), a surrogate indicator for unhealthy lifestyles, and a number of genetic loci, but the combined effect of MetS and genetic variants on GI cancer risk is uncertain. Methods: We included 430,036 participants with available MetS and genotype data from UK Biobank. During the follow‐up time, 5494 incident GI cancer cases, including esophageal cancer, gastric cancer, and colorectal cancer, were identified. We created a GI polygenic risk score (GI‐PRS) for overall GI cancer derived from three site‐specific cancer PRSs. Cox proportional hazards regression was used to estimate the associations of MetS and GI‐PRS with the risk of GI cancer. Results: MetS was significantly associated with 28% increment in GI cancer risk (hazard ratio [HR]MetS vs. non‐MetS: 1.28, 95% confidence interval [CI]: 1.21–1.35, p < 0.0001), whereas a high GI‐PRS (top quintile) was associated with 2.28‐fold increase in risk (HRhigh vs. low: 2.28, 95% CI: 2.09–2.49, p < 0.0001). Compared with participants without MetS and at low genetic risk (bottom quintile of GI‐PRS), those with MetS and at high genetic risk had 2.75‐fold increase in GI cancer risk (HR: 2.75, 95% CI: 2.43–3.12, p < 0.0001). Additionally, MetS in comparison with no MetS had 1.49‰, 2.75‰, and 3.37‰ absolute risk increases in 5 years among participants at low, intermediate (quintiles 2–4 of GI‐PRS) and high genetic risk, respectively, representing the number of subjects diagnosed as MetS causing a new GI cancer case in 5 years were 669, 364, and 296, respectively. Conclusions: Metabolic and genetic factors may jointly contribute to GI cancer risk and may serve as predictors by quantitative measurements to identify high‐risk populations of GI cancer for precise prevention. [ABSTRACT FROM AUTHOR]

Background: Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer., Methods: Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs)., Results: Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18-1.27) in men, and 1.26 (1.22-1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10-2.51) for men and 1.94 (1.78-2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = -1.01 in men, p<0.001; Beta = -0.98 in women, p<0.001)., Conclusions: Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle., Funding: This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ)., Competing Interests: LB, ZM, XF, CJ, TW, CY, JD, HM, ZH, HS, LW, MZ, GJ No competing interests declared, (© 2024, Bian, Ma et al.)

Dietary and genetic factors are considered to be associated with UGI cancer risk. However, examinations of the effect of healthy diet on UGI cancer risk and the extent to which healthy diet modifies the impact of genetic susceptibility on UGI cancer remains limited. Associations were analyzed through Cox regression of the UK Biobank data ( n = 415,589). Healthy diet, based on "healthy diet score," was determined according to fruit, vegetables, grains, fish, and meat consumption. We compared adherence to healthy diet and the risk of UGI cancer. We also constructed a UGI polygenic risk score (UGI-PRS) to assess the combined effect of genetic risk and healthy diet. For the results high adherence to healthy diet reduced 24% UGI cancer risk (HR high-quality diet : 0.76 (0.62-0.93), p = 0.009). A combined effect of high genetic risk and unhealthy diet on UGI cancer risk was observed, with HR reaching 1.60 (1.20-2.13, p = 0.001). Among participants with high genetic risk, the absolute five-year incidence risk of UGI cancer was significantly reduced, from 0.16% to 0.10%, by having a healthy diet. In summary, healthy diet decreased UGI cancer risk, and individuals with high genetic risk can attenuate UGI cancer risk by adopting a healthy diet.

Cancer site-specific polygenic risk scores (PRS) effectively identify individuals at high risk of individual cancers, but the effectiveness of PRS on overall cancer risk assessment and the extent to which a high genetic risk of overall cancer can be offset by a healthy lifestyle remain unclear. Here, we constructed an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific PRSs. Lifestyle was determined according to smoking, alcohol consumption, physical activity, body mass index, and diet. Cox regression by sex was used to analyze associations of genetic and lifestyle factors with cancer incidence using UK Biobank data ( N = 442,501). Compared with participants at low genetic risk (bottom quintile of CPRS), those at intermediate (quintiles 2 to 4) or high (top quintile) genetic risk had HRs of 1.27 (95% confidence interval, 1.21-1.34) or 1.91 (1.81-2.02) for overall cancer, respectively, for men, and 1.21 (1.16-1.27) or 1.62 (1.54-1.71), respectively, for women. A joint effect of genetic and lifestyle factors on overall cancer risk was observed, with HRs reaching 2.99 (2.45-3.64) for men and 2.38 (2.05-2.76) for women with high genetic risk and unfavorable lifestyle compared with those with low genetic risk and favorable lifestyle. Among participants at high genetic risk, the standardized 5-year cancer incidence was significantly reduced from 7.23% to 5.51% for men and from 5.77% to 3.69% for women having a favorable lifestyle. In summary, individuals at high genetic risk of overall cancer can be identified by CPRS, and risk can be attenuated by adopting a healthy lifestyle. SIGNIFICANCE: A new indicator of cancer polygenic risk score measures genetic risk for overall cancer, which could identify individuals with high cancer risk to facilitate decision-making about lifestyle modifications for personalized prevention., (©2021 American Association for Cancer Research.)