Metabolic Syndrome, Component Burden, and Incident Gastric Cancer Risk: A Prospective Cohort Study in the UK Biobank

Joint Effects of Metabolic Syndrome and Polygenic Risk Score on Lung Cancer Incidence and Mortality: A Prospective Cohort Study.

Cardiovascular–Kidney–Metabolic Syndrome Severity and Risk of Pancreatic Cancer in a Large Prospective Cohort

ABSTRACT Aims Pancreatic cancer remains one of the most lethal malignancies due to late diagnosis and limited opportunities for prevention. Cardiovascular–kidney–metabolic (CKM) syndrome reflects the cumulative burden of metabolic, renal, and cardiovascular dysfunction, but its association with pancreatic cancer risk has not been well established. We investigated this relationship in a large prospective cohort from the UK Biobank. Materials and Methods Participants without pancreatic cancer at baseline (2006–2010) were followed through national cancer and mortality registries until 31 December 2022. CKM syndrome was categorised into five stages (0–4) according to American Heart Association criteria. Incident pancreatic cancer was identified using ICD‐9 and ICD‐10 codes. Fine–Gray subdistribution hazard models accounting for death were used to estimate subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs), with prespecified subgroup analyses performed. Results Among 326,148 participants, 1234 incident pancreatic cancer cases were identified over a mean follow‐up of 13.5 years (SD 2.0). Incidence rates increased progressively from 9.0 to 48.6 per 100,000 person‐years across CKM stages. Compared with CKM stage 0, multivariable‐adjusted SHRs for pancreatic cancer were 1.97 (95% CI 1.28–3.02) for stage 1, 2.02 (1.42–2.87) for stage 2, and 2.08 (1.42–3.04) for stages 3–4 (p for trend < 0.001). Associations were generally consistent across subgroup analyses according to age, sex, smoking status, and alcohol consumption, without statistically significant interaction effects. Conclusions Advanced CKM syndrome was independently associated with higher pancreatic cancer risk, supporting its potential role in risk stratification and early detection strategies.

Association of the C-reactive protein–triglyceride–glucose index with the risk of incident cardiovascular disease in rectal cancer survivors

Background and objective Rectal cancer survivors face an elevated cardiovascular disease (CVD) burden shaped by tumor- and treatment-related pathophysiology beyond conventional risk factors. We evaluated the association between the C-reactive protein–triglyceride–glucose index (CTI)—a composite inflammatory–metabolic indicator—and incident CVD in this population. Methods This retrospective cohort study enrolled 1,160 rectal cancer survivors from a Chinese tertiary hospital as the discovery cohort and 1,752 from the UK Biobank as an independent validation cohort. Incident CVD was the primary outcome. Multivariable logistic regression, restricted cubic splines, and model performance metrics were used to assess the association, dose–response relationship, and incremental predictive value of CTI. Results After full multivariable adjustment, each one-SD increment in CTI was associated with an 18% higher risk of incident CVD (OR = 1.18, 95% CI: 1.02–1.36, p = 0.025), with an approximately linear dose–response relationship (p for non-linearity = 0.448) and excess risk concentrated in the highest quartile (Q4 vs. Q1: OR = 1.60, 95% CI: 1.07–2.42, p = 0.024). Adding CTI improved discrimination (AUC = 0.718) beyond the CRP-based model (AUC = 0.713, p = 0.050) and the TyG-based model (AUC = 0.715, p = 0.042), and significantly improved risk reclassification (categorical NRI = 0.052, 95% CI: 0.018–0.086, p = 0.005). The association was stronger in patients aged <65 years (OR = 1.63; p for interaction = 0.007) and those without baseline hypertension (OR = 1.33; p for interaction = 0.034). In the UK Biobank cohort, the CTI–CVD association attenuated progressively and became non-significant after full adjustment (OR = 1.08, 95% CI: 0.95–1.22, p = 0.261; AUC = 0.649). Conclusion CTI was independently associated with incident CVD in rectal cancer survivors and improved risk reclassification beyond CRP or TyG alone, with effects concentrated in younger and non-hypertensive patients. Its incremental value attenuated in a community-based population, suggesting that CTI is most informative in oncology settings with high inflammatory–metabolic burden.

Cardiovascular-kidney-metabolic health, genetic susceptibility, and incident cancer risk: a prospective UK biobank cohort and machine learning study

Background It remains unclear whether cardiovascular-kidney-metabolic (CKM) syndrome and genetic susceptibility are associated with cancer incidence. This study aims to evaluate the associations between CKM health status, genetic susceptibility, and cancer incidence, and to develop a machine learning-based prediction model for cancer risk in patients with advanced CKM syndrome. Methods This study included 399,034 UK Biobank participants (389,289 with genetic data). CKM health was categorized into stages 0–4. Genetic susceptibility was assessed via a polygenic risk score (PRS). Associations were evaluated using Cox proportional hazard models. For participants with advanced CKM, candidate predictors were screened via the Boruta algorithm, LASSO regression, and multivariable logistic regression. Eight machine learning models were constructed and validated, and their predictive discrimination, calibration performance, and clinical practical value were further assessed. Additionally, Shapley Additive Explanations (SHAP) were adopted to interpret the internal mechanism of the optimal model. The dose–response relationship was assessed using restricted cubic splines (RCS), and mediation analysis was further performed to explore the underlying mechanism of the observed associations. Results During a median follow-up of 13.7 years, 48,247 incident cancer cases were identified. Compared to CKM stage 0, multivariable-adjusted hazard ratios (HRs) were 1.01 (95% CI: 0.91-1.12) for stage 1, 1.21 (1.10–1.33) for stage 2, and 2.17 (1.95–2.42) for advanced CKM (stage 3–4). Participants with high PRS and advanced CKM faced the highest cancer risk (HR 3.24, 95% CI 2.68–3.93). A total of 14 predictors were retained after screening. The GBM model achieved the best predictive performance (test AUC = 0.801). A web-based calculator was developed to realize individualized cancer risk prediction. RCS analyses indicated that diastolic blood pressure (Pnonlinearity<0.05), neutrophil count(Pnonlinearity<0.05), alkaline phosphatase (Pnonlinearity=0.001), and TyG-BMI (Pnonlinearity<0.05) were significantly and nonlinearly associated with cancer risk. Total bilirubin the strongest positive mediating effect, explaining 44.45% of the total association (P < 0.001). Conclusions Advanced CKM syndrome independently increases incident cancer risk, and this elevated risk is significantly amplified by high genetic susceptibility. The validated GBM model provides an interpretable tool for individualized risk estimation, which serves as a valuable complementary tool for clinical risk stratification and cancer patients with, cancer.

The Association of Diabetes-related Dietary Patterns with Pancreatic Cancer Risk in the European Prospective Investigation into Cancer and Nutrition study.

BACKGROUND Pancreatic cancer is relatively rare but remains one of the most lethal tumors. Identifying modifiable risk factors is a crucial step to reduce disease burden. Evidence suggests a potential role of type 2 diabetes mellitus in its pathogenesis. OBJECTIVE To examine the association between dietary patterns related to diabetes and pancreatic cancer risk in a European population. METHODS A total of 367,395 participants from the European Prospective Investigation into Cancer and Nutrition study were included. After a median follow-up of 14.9 years, 926 incident cases were identified. The Diabetes Risk Reduction Diet (DRRD), the Empirical Dietary Index for Hyperinsulinemia (EDIH) and the Empirical Dietary Index for Insulin Resistance (EDIR) were estimated from food frequency questionnaires at recruitment. Hazard ratios (HRs) and 95% confidence intervals (CI) for the association between dietary patterns and pancreatic cancer were calculated using multivariable Cox proportional hazards regression models, adjusted for relevant confounders. RESULTS Adherence to DRRD showed no association with risk of pancreatic cancer (HRT3vsT1 = 0.94, 95% CI 0.79-1.12). Higher adherence to EDIH was associated with a borderline 19% increased pancreatic cancer risk (HRT3vsT1 = 1.19, 95% CI 0.99-1.44). No significant associations were observed in relation to EDIR. No heterogeneity was observed among the subgroups. CONCLUSIONS Higher adherence to a hyperinsulinemic dietary pattern may contribute to the risk of developing pancreatic cancer in our population. Further research is warranted to elucidate the potential role of dietary factors in cancer risk prevention.

Age- and sex-dependent associations of metabolic syndrome with colorectal cancer in the UK Biobank.

BACKGROUND The concurrent rise in metabolic syndrome (MetS) and the changing age profile of colorectal cancer (CRC) necessitates clarifying the heterogeneity in their association across demographic groups. This study aimed to define the precise age- and sex-specific associations between MetS and CRC risk, addressing a key gap to inform targeted prevention paradigms. METHODS In this cohort study, we analysed data from UK Biobank participants aged 40-69 years (recruited 2006-2010). Participants were stratified by age (<60 or ≥60 years) and sex into four groups. Multivariable Cox proportional hazards models were used to assess the associations of MetS, the number of metabolic abnormalities, and each component with CRC incidence. RESULTS Among 379,173 participants, 4971 developed CRC during a median follow-up of 11.8 years. MetS was most strongly associated with CRC in younger males (hazard ratio [HR] 1.31, 95% CI 1.15-1.50), significantly in older adults of both males (HR 1.18, 95% CI 1.07-1.30) and females (HR 1.18, 95% CI 1.05-1.33), but not in younger females (HR 1.05, 95% CI 0.89-1.25). Older males but not females showed increasing risks when having 3, 4, and 5 abnormalities compared to none, respectively. Beyond younger females, elevated waist circumference was the sole component consistently linked to higher risk. CONCLUSIONS The association between MetS and CRC is strongly dependent on age and sex in White populations, with the highest risk concentrated in young and middle-aged males. These findings directly support risk-stratified prevention and provide crucial clues for investigating the underlying sex- and age-specific biological mechanisms.