AIM:We investigated associations between consensus molecular subtype (CMS) and colon cancer recurrence, and explored how the inflammatory potential of diet and lifestyle relate to recurrence across CMS subgroups. METHODS:A nested case-control study was implemented in two prospective cohorts of colon cancer patients. Cases were patients with recurrence (n = 167), and controls (n = 668) were matched using incidence density sampling. Formalin-fixed paraffin-embedded tumour tissue was used to determine image-based CMS (imCMS) from hematoxylin and eosin-stained sections using a deep learning model. Lifestyle factors and dietary intake were assessed at diagnosis using questionnaires to construct the lifestyle inflammation score (LIS) and the dietary inflammation score (DIS). Associations between imCMS, DIS, LIS and recurrence were investigated using multivariable conditional logistic regression analyses. RESULTS:Patients with an imCMS4 compared to those with an imCMS2 tumour had a higher risk of recurrence (IRRper_1_unit_increase 2.22, 95%CI 1.28; 3.85). A higher DIS was not associated with recurrence (IRRper_1_unit_increase 1.04, 95%CI 0.96; 1.12), while the risk of recurrence was higher in patients with a higher LIS (IRRper_1_unit_increase 1.21, 95%CI 0.97; 1.52), albeit non-significant. In the subgroup of patients with an imCMS4 tumour, a higher DIS was associated with a 39% higher risk of recurrence (I IRRper_1_unit_increase 1.39, 95%CI 1.08; 1.78). Associations between the LIS and risk of recurrence were not clearly different across imCMS subgroups. CONCLUSION:Individuals with an imCMS4 tumour had the highest risk of a recurrence. In addition, the inflammatory potential of the diet was associated with recurrence only in patients with imCMS4.

Supplementary Table S7. Confounding analyses for the association between the interaction of the TGF-B-Polygenic Risk Score and red meat intake in relation to colorectal cancer risk.

Background Liver fat accumulation has been associated with impaired colorectal cancer prognosis. Associations may differ for colon and rectal cancer due to different disease mechanisms and dissemination patterns. Here, we investigated associations between liver fat and cancer recurrence, recurrence-free survival (RFS), and overall survival (OS) among 1596 individuals with stage I-III colon or rectal cancer.Methods Within a prospective cohort study, we used data from adults recently diagnosed with colon (n = 1080) or rectal (n = 516) cancer. Liver fat was evaluated using routine contrast-enhanced computed tomography (CT)-scans taken at diagnosis. Cox proportional hazards regression analyses adjusted for clinical and lifestyle-related variables were used to obtain hazard ratios (HRs) and 95% confidence intervals (95% CIs).Results During a median follow-up of 6.4 and 8.8 years, 247 (15%) recurrences (12% for colon and 22% for rectal cancer) and 418 (26%) deaths (25% for colon and 29% for rectal cancer) occurred, respectively. More liver fat was associated with an increased recurrence risk (HRT3vsT1 = 1.60, 95% CI = 1.02 to 2.50), worse RFS (HRT3vsT1 = 1.45, 95% CI = 1.05 to 2.00), and OS (HRT3vsT1 = 1.67, 95% CI = 1.20 to 2.33) among individuals with colon cancer. Liver fat was not associated with recurrence (HRT3vsT1 = 0.70, 95% CI = 0.42 to 1.18), RFS (HRT3vsT1 = 0.87, 95% CI = 0.59 to 1.30), or OS (HRT3vsT1 = 1.15, 95% CI = 0.74 to 1.80) among individuals with rectal cancer.Conclusion More liver fat was associated with poor clinical outcomes in patients with stage I-III colon cancer. Further studies are needed to confirm these findings and explore mechanistic routes linking liver fat to colon cancer prognosis.

Supplementary Figure S1, LocusZoom plots.

Supplementary Table S3. Weights used for polygenic risk score estimation and coordinates from single nucleotide polymorphisms considered in the study.

BACKGROUND:Fish intake may exert antineoplastic effects, potentially through omega-3 fatty acids. However, its role in the development of colorectal neoplasms (CRNs) among individuals with Lynch syndrome (LS), a genetic predisposition to colorectal cancer, remains unclear. OBJECTIVES:The aim of this study was to examine the association between fish intake and CRN risk among LS carriers, overall and across subgroups defined by nonsteroidal anti-inflammatory drug/aspirin use, sex, geographical region, CRN history, and pathogenic variant type, and to examine associations between fish types and CRN risk. METHODS:Data from 1816 confirmed LS carriers in the GEOLynch cohort (The Netherlands) and the Colon Cancer Family Registry (Australia, Canada, and the United States) were used. Information on fish intake was collected at inclusion using food frequency questionnaires. CRNs included adenoma, serrated lesions, and colorectal cancer. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) across sex-specific quartiles and per 10 g/d of total fish intake. Associations for specific fish types were assessed per 5 g/d increase. RESULTS:During a median follow-up time of 7.0 y (IQR range: 2.8-13.6), 742 (40.9%) participants developed a CRN. The CRN risk was similar in individuals in the highest quartile of fish intake compared with the lowest quartile (HR 1.03; 95% CI: 0.81, 1.32). No association was observed for every 10 g/d increment in fish intake (HR: 1.0; 95% CI: 0.95, 1.05) and across subgroups. However, a 5 g/d increase in canned fish appeared to increase the risk of CRNs (HR: 1.06; 95% CI: 1.01, 1.10). CONCLUSIONS:Total fish intake does not appear to influence the development of CRNs in individuals with LS, whereas the influence of canned fish intake on CRN risk should be further investigated.

Supplementary Table S5. Results from multinomial logistic regression models to evaluate pathway-based polygenic risk score interactions with red meat and processed meat intake by topological tumor location.

Supplementary Table S6. Associations between red meat/processed meat intake with colorectal cancer risk stratified by quartiles of pathway-based polygenic risk scores.

Abstract Objective To examine associations of BMI-related polygenic scores (PGSs) with BMI-for-age z-score (BMIz), height-for-age z-score (HAZ), and weight; assess sex-specific effects; and test PGS-by-diet interactions in youth experiencing the double burden of malnutrition. Methods In this cross-sectional study of Filipino youth aged 6-19 years, we analyzed genome-wide genotype, anthropometric, and dietary data from two 24-hour recalls. Four ancestry-standardized BMI PGSs were evaluated using linear regression adjusted for age, sex, and ancestry principal components, with platform-specific estimates combined by fixed-effects meta-analysis. Results All four PGSs were positively associated with BMIz (β range: 0.119 – 0.320). The strongest association was observed for the multi-ancestry score PGS005202 (β = 0.320; P = 2.39 x 10 -9 ; ΔR 2 = 4.98%). No PGS was associated with HAZ. PGS005202 and PGS005279 were associated with higher weight independent of HAZ. A significant PGS000716-by-sex interaction was observed for BMIz (q = 0.034), with an association in boys (β = 0.253; P = 0.002) but not in girls (β = -0.007; P = 0.93). No PGS-by-diet interaction remained significant after multiple-testing correction. Conclusions BMI-related PGSs were associated with adiposity-related traits, but not linear growth, in Filipino youth. Findings support sex-stratified analyses and further evaluation of ancestry-inclusive PGSs in similar pediatric settings.

Supplementary Table S4. Pathway annotation, mapped genes, and putative effect for single nucleotide polymorphisms that were overrepresented in PANTHER pathways.

A healthy lifestyle and diet may improve outcomes of patients with non-muscle invasive bladder cancer (NMIBC), potentially through reducing systemic inflammation. Therefore, this study investigated the association of a post-diagnosis Lifestyle (LIS) and Dietary Inflammation Score (DIS), and high-sensitivity C-reactive protein (hsCRP) with the risks of NMIBC recurrence and progression. Patients with newly diagnosed NMIBC between 2014 and 2021 were recruited for the prospective multi-center cohort UroLife. Lifestyle (n = 1334) and/or diet (n = 1306) were self-reported at 3 months post-diagnosis using lifestyle and food frequency questionnaires. The LIS and DIS were calculated to capture the inflammatory potential of lifestyle and diet; higher scores indicate more pro-inflammatory exposures. Plasma hsCRP was measured at 3 months postdiagnosis. The association of LIS and DIS with hsCRP was ascertained in multivariable linear regression models. The association of the LIS, DIS, and hsCRP with risks of first or multiple recurrence(s), and stage and/or grade progression was assessed using multivariable Cox proportional hazards models. Over a median follow-up time of 4.7 years, 466 patients had at least one recurrence, and 155 had progression. Each 1-point increment in LIS and DIS was associated with a 43% (95% CI 29%-58%) and 6% (95% CI 3%-10%) increase in hsCRP, respectively. Higher LIS, DIS, and hsCRP were not associated with risks of first or multiple recurrence(s), and progression. In conclusion, a pro-inflammatory lifestyle and diet, and systemic inflammation, as measured by hsCRP, were not associated with NMIBC outcomes in our cohort. Yet, contributions from specific inflammatory processes or other biomarkers cannot be excluded.

AbstractBackground: Red meat and/or processed meat are established colorectal cancer risk factors. Genome-wide association studies (GWAS) have reported more than 200 variants associated with colorectal cancer risk. We used functional annotation data to identify subsets of variants within known pathways to construct pathway-based polygenic risk scores (pPRS) to assess interactions with meat intake. Methods: A pooled sample of 30,812 cases and 40,504 colorectal cancer controls from 27 studies was analyzed. Quantiles for red and processed meat intake were constructed. A total of 204 GWAS variants were annotated to genes with Annotation Query (AnnoQ) and assessed for overrepresentation in PANTHER-reported pathways. pPRSs were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated interactions between pPRS and red or processed meat intake in relation to colorectal cancer risk. Results: A total of 30 variants were overrepresented in four pathways: presenilin/Alzheimer disease, cadherin/WNT signaling, gonadotropin-releasing hormone receptor, and transforming growth factor-β (TGF-β) signaling. We found a significant interaction between TGF-β pPRS and red meat intake [ORint = 0.95; 95% confidence interval (CI) = 0.92–0.98; P = 0.003). When variants in the TGF-β pathway were assessed, we observed significant interactions of red meat with rs2337113 [intron SMAD family member 7 (SMAD7) gene, Chr18] and rs2208603 [intergenic region bone morphogenetic protein 5 (BMP5), Chr6; P = 0.0005 and 0.036, respectively]. There was no evidence of pPRS × red meat interactions for other pathways or with processed meat. Conclusions: This pathway-based interaction analysis revealed a statistically significant interaction between variants in the TGF-β pathway and red meat consumption that influences colorectal cancer risk. Impact: These findings shed light on the possible mechanistic link between red meat consumption and colorectal cancer risk.

Supplementary Table S2. Summary statistics for colorectal cancer-related risk factors in study participants.

Physical activity is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–physical activity interaction analysis. Using logistic regression (1-d.f), two-step screening and testing method (EDGE), and joint tests (3-d.f), we analyzed interactions between common genetic variants across the genome and physical activity in relation to CRC risk. Self-reported physical activity levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk; 39,992 participants) and as study- and sex-specific quartiles of activity (42,602 participants). Physical activity was inversely associated with CRC risk overall (OR [active vs. inactive] = 0.85; 95

BACKGROUND:To enable fast and individual assessment of adherence to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Cancer Prevention Recommendations, the WCRF/AICR Screener (hereafter Screener) was developed and validated. Although the recommendations are grounded in strong epidemiologic evidence, this study evaluated the external applicability of the Screener, including its association with all-cause mortality, variable contribution, and prognostic performance compared with the standard 2018 WCRF/AICR Score (hereafter Score). METHODS:We analyzed 1919 patients with newly diagnosed stages I-IV colorectal cancer from the prospective Dutch COLON study. Adherence to the recommendations was assessed at diagnosis using the algorithm from the Screener and, for comparison, the Score. Primary outcome was all-cause mortality. Cox proportional hazards models estimated HRs and 95% confidence intervals (CI) for mortality per 1-SD increase and across quartiles. Models were adjusted for potential confounders. Leave-one-out analysis evaluated individual variable contribution. RESULTS:A total of 533 deaths occurred during a median follow-up of 8.3 years. Greater adherence (highest vs. lowest quartile) to the Screener was associated with lower all-cause mortality (HR: 0.73; 95% CI, 0.57-0.93). Comparable associations were observed for the Score (HR: 0.82; 95% CI, 0.64-1.05). CONCLUSIONS:The Screener showed comparable performance and external applicability to the Score in relation to all-cause mortality among patients with colorectal cancer. IMPACT:The Screener may facilitate brief and practical lifestyle assessment in clinical and research settings, supporting risk stratification and integration of lifestyle evaluation into survivorship care.

Supplementary Table S1. Distribution of cases and controls by participating studies, genotyping platform, and study site.

Gene-based nutrition recommendations have emerged as a strategy for weight management, but evidence of their added value over standard advice remains inconclusive. This randomized controlled trial evaluated the effects of MyGeneMyDiet®, a genotype-informed lifestyle program, compared with standard recommendations on anthropometric, biochemical, and dietary outcomes in Filipino adults with overweight and obesity over 12 months. In this randomized controlled trial, participants received either MyGeneMyDiet® or standard recommendation (control). Both groups underwent regular nutrition counseling during the active phase (months 0–6) before transitioning to an inactive phase (free-living conditions, months 6–12). Primary outcomes included weight, BMI, waist circumference, and body fat percentage; secondary outcomes were dietary intake and biochemical markers. Analyses were conducted according to randomized group assignment. Primary analyses used available case-data at each timepoint, with paired t-tests for within-group comparisons and ANCOVA for between-group differences. Sensitivity analyses used Last Observation Carried Forward (LOCF) and Inverse Probability of Attrition Weighting (IPAW) to address loss-to-follow-up. Of the 136 screened, 52 initiated the intervention (MyGeneMyDiet®, n = 29; standard recommendation, n = 23), and 27 completed the 12-month follow-up (MyGeneMyDiet®, n = 15; standard recommendation, n = 12). Both groups lost weight over 12 months, with no evidence of meaningful between-group differences. During the 6-month active phase, baseline-adjusted analyses showed no significant between-group differences in weight (-0.36 kg [95

BACKGROUND:One-carbon metabolism (OCM) is a target of the chemotherapeutic agent capecitabine. OBJECTIVES:We investigated OCM biomarker concentrations in relation to capecitabine-induced toxicities in patients with stage II-III colorectal cancer. METHODS:Within a prospective cohort, 297 patients receiving adjuvant capecitabine-based chemotherapy were included. Pretreatment plasma concentrations of the OCM biomarkers folate, vitamin B2, vitamin B6, vitamin B12, total homocysteine, methionine, serine, and glycine were determined. We also investigated whether associations differed according to methylenetetrahydrofolate reductase (MTHFR) C677T genotypes. Chemotherapy-induced toxicities were defined as toxicity-induced modifications of capecitabine treatment. To allow for inspection of shapes of the associations, restricted cubic splines and Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age and sex. RESULTS:In total, 156 (53%) patients experienced toxicity-induced modifications of capecitabine treatment. Folate was not associated with toxicities in the overall population. Higher folate concentrations were associated with a lower risk of toxicities in patients with MTHFR C677T CT/TT genotype (HRperdoubling: 0.75; 95% CI: 0.57, 0.98) but not in patients with CC genotype (HRperdoubling: 1.17; 95% CI: 0.84, 1.63). Higher concentrations of vitamin B2 were associated with a lower risk of toxicities (HRperdoubling: 0.81; 95% CI: 0.67, 0.99), whereas higher glycine concentrations were associated with a higher risk of toxicities (HRperdoubling: 1.87; 95% CI: 1.18, 2.94). The association between vitamin B6 and vitamin B12 and toxicities appeared nonlinear. Homocysteine, methionine, and serine were not associated with toxicities. CONCLUSIONS:Future studies investigating whether nutrition-guided optimization of OCM biomarkers will result in improved treatment tolerance are warranted.

Supplementary Table S4 lists the 140 colorectal-cancer-associated loci and associations with colorectal cancer in European-ancestry population.

Supplementary Figure S6 shows the calibration on relative risk of PRS stratified by PRS with 7 bins in groups of different ancestry in the GERA cohort.