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Evidence indicates that combinations of anti-EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)-low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS-wild-type tumors (31%). KRAS c.34G>T mutants showed higher CIMP-high prevalence (14%) and lower CIMP-negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T-mutated tumors were associated with cecal location, non-microsatellite instability (MSI)-high status, BRAF wild type, and PIK3CA mutation when compared with KRAS-wild-type tumors. Compared with BRAF-mutated tumors, KRAS c.34G>T mutants showed more frequent LINE-1 hypomethylation, a biomarker for early-onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum (F. animalis), pks + Escherichia coli, Bifidobacterium, or (enterotoxigenic) Bacteroides fragilis. Among 1122 BRAF-wild-type colorectal carcinomas, compared with KRAS-wild-type tumors, multivariable-adjusted colorectal cancer-specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05-3.17) in KRAS c.34G>T (p.G12C)-mutated tumors (p = 0.035) and 1.57 (1.22-2.02) in other KRAS-mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We investigated associations between diabetes and mortality among participants with incident colorectal cancer (CRC) from the Southern Community Cohort Study., Methods: Participants (73% non-Hispanic Black; 60% income < $15,000) were recruited between 2002-2009. Diabetes was self-reported at enrollment and follow-up surveys at approximately 5-year intervals. Incident CRC and mortality were identified via state registries and the National Death Index. Proportional hazards models calculated associations between diabetes with overall, CRC-specific mortality among 1059 participants with incident CRC., Results: Diabetes prior to diagnosis is associated with elevated overall (hazard ratio [95% confidence interval]: (1.46[1.22-1.75]), and CRC-specific mortality (1.36[1.06-1.74])) after adjustment for tumor stage. For non-Hispanic Black and non-Hispanic White participants, consistent associations were observed for overall (1.35[1.10-1.66] vs. 1.89[1.31-2.72], respectively, p-interaction = 0.11) and CRC-specific mortality (1.30[0.99-1.71] vs. 1.77[1.06-2.95], respectively, p-interaction = 0.28). For individuals with incomes <$15,000/year, associations with overall (1.44[1.15-1.79]) and CRC-specific mortality (1.28[0.94-1.73]) were similar to the full sample. Associations with overall (1.71[1.37-2.13]) and CRC-specific mortality (1.65[1.22-2.22]) were highest for diabetes ≥ 10 years at diagnosis., Conclusions: Pre-diagnosis diabetes is associated with higher mortality among participants with incident CRC from a predominantly non-Hispanic Black cohort with lower socioeconomic status. The higher prevalence of diabetes in this population may contribute to racial disparities in CRC mortality., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

It remains unclear if pre-diagnostic factors influence the developmental pathways of colorectal cancer (CRC) that could enhance tumor aggressiveness. This study used prospective data from 205,489 cancer-free US health professionals to investigate the associations of 31 known or putative risk factors with the risk of aggressive CRC. Tumor aggressiveness was characterized by three endpoints: aggressive CRC (cancer that causes death within 5 years of diagnosis), fatal CRC, and tumor stage at diagnosis. The data augmentation method was used to assess the difference in the associations between risk factors and endpoints. We documented 3201 CRC cases, of which 899 were aggressive. The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non-aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non-aggressive CRC (p Heterogeneity <0.05). Lower intake of whole grains or cereal fiber and greater dietary inflammatory potential were associated with a higher risk of aggressive but not non-aggressive CRC. The remaining risk factors showed comparable associations with aggressive CRC and non-aggressive CRC. Aggressive cases were more likely to have KRAS-mutated tumors but less likely to have distal or MSI-high tumors (p < .007). Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre-diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions., (© 2024 UICC.)

Importance: Aspirin reduces the risk of colorectal cancer (CRC). Identifying individuals more likely to benefit from regular aspirin use for CRC prevention is a high priority., Objective: To assess whether aspirin use is associated with the risk of CRC across different lifestyle risk factors., Design, Setting, and Participants: A prospective cohort study among women in the Nurses' Health Study (1980-2018) and men in the Health Professionals Follow-Up Study (1986-2018) was conducted. Data analysis was performed from October 1, 2021, to May 22, 2023., Exposures: A healthy lifestyle score was calculated based on body mass index, alcohol intake, physical activity, diet, and smoking with scores ranging from 0 to 5 (higher values corresponding to a healthier lifestyle). Regular aspirin use was defined as 2 or more standard tablets (325 mg) per week., Main Outcome and Measures: Outcomes included multivariable-adjusted 10-year cumulative incidence of CRC, absolute risk reduction (ARR), and number needed to treat associated with regular aspirin use by lifestyle score and multivariable-adjusted hazard ratios for incident CRC across lifestyle scores., Results: The mean (SD) baseline age of the 107 655 study participants (63 957 women from the Nurses' Health Study and 43 698 men from the Health Professionals Follow-Up Study) was 49.4 (9.0) years. During 3 038 215 person-years of follow-up, 2544 incident cases of CRC were documented. The 10-year cumulative CRC incidence was 1.98% (95% CI, 1.44%-2.51%) among participants who regularly used aspirin compared with 2.95% (95% CI, 2.31%-3.58%) among those who did not use aspirin, corresponding to an ARR of 0.97%. The ARR associated with aspirin use was greatest among those with the unhealthiest lifestyle scores and progressively decreased with healthier lifestyle scores (P < .001 for additive interaction). The 10-year ARR for lifestyle scores 0 to 1 (unhealthiest) was 1.28%. In contrast, the 10-year ARR for lifestyle scores 4 to 5 (healthiest) was 0.11%. The 10-year number needed to treat with aspirin was 78 for participants with lifestyle scores 0 to 1, 164 for score 2, 154 for score 3, and 909 for scores 4 to 5. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for body mass index and smoking., Conclusions and Relevance: In this cohort study, aspirin use was associated with a greater absolute reduction in risk of CRC among individuals with less healthy lifestyles. The findings of the study suggest that lifestyle risk factors may be useful to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.

Previous solid organ transplantation has been associated with worse survival among colorectal cancer (CRC) patients. This study investigates the contribution of CRC characteristics and treatment-related factors to the differential survival. Using the Swedish register-linkage CRCBaSe, all patients with solid organ transplantation before CRC diagnosis were identified and matched with non-transplanted CRC patients. Associations between transplantation history and clinical CRC factors and survival were estimated using the Kaplan-Meier estimator and logistic, multinomial, and Cox regression, respectively. Ninety-eight transplanted and 474 non-transplanted CRC patients were followed for 5 years after diagnosis. Among patients with stage I-III cancer, transplanted patients had lower odds of treatment with abdominal surgery [odds ratio (OR):0.27, 95% confidence interval (CI):0.08-0.90], than non-transplanted patients. Among those treated with surgery, transplanted colon cancer patients had lower odds of receiving adjuvant chemotherapy (OR:0.31, 95% CI:0.11-0.85), and transplanted rectal cancer patients had higher rate of relapse (hazard ratio:9.60, 95% CI:1.84-50.1), than non-transplanted patients. Five-year cancer-specific and overall survival was 56% and 35% among transplanted CRC patients, and 68% and 57% among non-transplanted. Accordingly, transplanted CRC patients were treated less intensely than non-transplanted patients, and had worse cancer-specific and overall survival. These patients might benefit from multidisciplinary evaluation including transplantation specialists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Benoni, Nordenvall, Hellström, Dietrich, Martling, Smedby and Eloranta.)

Background: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer., Objective: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing., Design: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors., Results: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways., Conclusions: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have reported the presence of JC virus (JCV) in human tumors, The association of JCV and CRC remains controversial. This study aimed to evaluate the rearranged NCCR region of the detected JCV DNA in CRC patients' tissue samples., Methods: In this case-control study, tumor tissues (n = 60), adjacent normal tissues (n = 60), and urine samples (n = 60) of the CRC patients were collected. The nested PCR was employed to detect the VP1 and NCCR regions of the JCV genome. The positive JCV PCR products were sequenced and a phylogenetic tree was constructed to determine the JCV genotypes. After extracting RNA and preparing cDNA, the expression of JCV LTAg was examined in 60 tumor tissues and 60 adjacent normal tissues. The analysis of JCV LTAg expression was performed using GraphPad Prism software version 8., Results: The analysis reveals that JCV DNA was detected in 35/60 (58.3%) tumor tissues, while 36/60 (60.0%) of adjacent normal tissues (p = 0.85). JCV DNA was detected in 42/60 (70.0%) urine samples when compared to 35/60 (58.3%) tumor tissues of CRC patients and was not found significant (P = 0.25). The phylogenetic tree analysis showed the dominant JCV genotype 3, followed by genotype 2D was distributed in tumor tissue, normal tissue, and urine samples of the CRC patients. Analysis of randomly selected NCCR sequences from JCV regions in tumor tissue samples revealed the presence of rearranged NCCR blocks of different lengths.: 431 bp, 292 bp, 449 bp, and 356 bp. These rearranged NCCR blocks differ from the rearranged NCCR blocks described in PML-type Mad-1, Mad-4, Mad-7, and Mad-8 prototypes. The expression of JCV LTAg was significantly different in tumor tissue compared to normal tissue, with a p-value of less than 0.002., Conclusion: A significant proportion of 35%> of the tumor tissue and urine samples of the CRC patients was found to be positive for JCV DNA (P = 0.25). The parallel analysis of tumor and urine samples for JCV DNA further supports the potential for non-invasive screening tools. This study provides new insights into Rearranged NCCR variant isolates from patients with CRC. The significant difference in JCV LTAg expression between tumor and normal tissue indicates a latent JCV status potentially leading to cancer development., (© 2024. The Author(s).)

Background: We determined the impact of an increased two-stool faecal immunochemical test (FIT) cut-off on colonoscopy positivity and relative sensitivity and specificity in the randomized controlled screening trial screening of Swedish colons conducted in Sweden., Methods: We performed a cross-sectional analysis of participants in the FIT arm that performed FIT between March 2014 and 2020 within the study registered with ClinicalTrials.gov, NCT02078804, who had a faecal haemoglobin concentration of at least 10 µg/g in at least one of two stool samples and who underwent a colonoscopy (n = 3841). For each increase in cut-off, we computed the positive predictive value (PPV), numbers needed to scope (NNS), sensitivity and specificity for finding colorectal cancer (CRC) and advanced neoplasia (AN; advanced adenoma or CRC) relative to cut-off 10 µg/g., Results: The PPV for AN increased from 23.0% (95% confidence intervals [CI]: 22.3%-23.6%) at cut-off 10 µg/g to 28.8% (95% CI: 27.8%-29.7%) and 33.1% (95% CI: 31.9%-34.4%) at cut-offs 20 and 40 µg/g, respectively, whereas the NNS to find a CRC correspondingly decreased from 41 to 27 and 19. The PPV for AN was higher in men than women at each cut-off, for example 31.5% (95% CI: 30.1%-32.8%) in men and 25.6% (95% CI: 24.3%-27.0%) in women at 20 µg/g. The relative sensitivity and relative specificity were similar in men and women at each cut-off., Conclusion: A low cut-off of around 20-40 µg/g allows detection and removal of many AN compared to 10 µg/g while reducing the number of colonoscopies in both men and women., (© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Importance: The global burden of obesity is increasing, as are colorectal cancer (CRC) incidence and mortality., Objectives: To assess the association between body mass index (BMI) and risks of incident CRC and CRC-related death in the Asian population., Design, Setting, and Participants: This cohort study includes data pooled from 17 prospective cohort studies included in The Asia Cohort Consortium. Cohort enrollment was conducted from January 1, 1984, to December 31, 2002. Median follow-up time was 15.2 years (IQR, 12.1-19.2 years). Data were analyzed from January 15, 2023, through January 15, 2024., Exposure: Body mass index, calculated as weight in kilograms divided by height in meters squared., Main Outcomes and Measures: The primary outcomes were CRC incidence and CRC-related mortality. The risk of events is reported as adjusted hazard ratios (AHRs) and 95% CIs for incident CRC and death from CRC using the Cox proportional hazards regression model., Results: To assess the risk of incident CRC, 619 981 participants (mean [SD] age, 53.8 [10.1] years; 52.0% female; 11 900 diagnosed incident CRC cases) were included in the study, and to assess CRC-related mortality, 650 195 participants (mean [SD] age, 53.5 [10.2] years; 51.9% female; 4550 identified CRC deaths) were included in the study. A positive association between BMI and risk of CRC was observed among participants with a BMI greater than 25.0 to 27.5 (AHR, 1.09 [95% CI, 1.03-1.16]), greater than 27.5 to 30.0 (AHR, 1.19 [95% CI, 1.11-1.29]), and greater than 30.0 (AHR, 1.32 [95% CI, 1.19-1.46]) compared with those with a BMI greater than 23.0 to 25.0 (P < .001 for trend), and BMI was associated with a greater increase in risk for colon cancer than for rectal cancer. A similar association between BMI and CRC-related death risk was observed among participants with a BMI greater than 27.5 (BMI >27.5-30.0: AHR, 1.18 [95% CI, 1.04-1.34]; BMI >30.0: AHR, 1.38 [95% CI, 1.18-1.62]; P < .001 for trend) and was present among men with a BMI greater than 30.0 (AHR, 1.87 [95% CI, 1.49-2.34]; P < .001 for trend) but not among women (P = .15 for trend) (P = .02 for heterogeneity)., Conclusions and Relevance: In this cohort study that included a pooled analysis of 17 cohort studies comprising participants across Asia, a positive association between BMI and CRC incidence and related mortality was found. The risk was greater among men and participants with colon cancer. These findings may have implications to better understand the burden of obesity on CRC incidence and related deaths in the Asian population.

Background: We examined whether the association between alcohol consumption and colorectal cancer (CRC) incidence was stronger for tumors with higher contributions of defective mismatch repair (dMMR)-related tumor mutational signatures., Methods: We used data from 227 916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 4 years through validated food frequency questionnaires. Relative contributions of 2 defective mismatch repair-related tumor mutational signatures with single-based substitutions (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC patients. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the tumor mutational signatures. All statistical tests were 2-sided., Results: We documented 825 incident CRC patients with available tumor mutational signature data over 26 to 36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (Ptrend = .02 for heterogeneity) compared with tumors with lower contributions of this tumor mutational signature. Compared with nondrinkers, drinkers who imbibed 15 g/d or more of alcohol had a high risk of c-dMMRb/SBS26-high CRC (multivariable-adjusted hazard ratio = 2.43, 95% confidence interval = 1.55 to 3.82) but not c-dMMRb/SBS26-low CRC (multivariable-adjusted hazard ratio = 0.86, 95% confidence interval = 0.57 to 1.28) or c-dMMRb/SBS26-moderate CRC (multivariable-adjusted hazard ratio = 1.14, 95% confidence interval = 0.76 to 1.71). No significant differential associations were observed for c-dMMRa/SBS15 (Ptrend = .41 for heterogeneity)., Conclusions: High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC., Methods: Metabolite quantitative trait loci were derived from 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC., Results: The study identified 30 plasma metabolites and 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to hip ratio, fasting insulin, smoking initiation) on CRC., Conclusion: This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Lymph node metastasis (LNM) occurs in 20-25% of patients with T2 colorectal cancer (CRC). Identification of risk factors for LNM in T2 CRC may help identify patients who are at low risk and thereby potential candidates for endoscopic full-thickness resection. We examined risk factors for LNM in T2 CRC with the goal of establishing further criteria of the indications for endoscopic resection., Methods: MEDLINE, CENTRAL, and EMBASE were systematically searched from inception to November 2023. Studies that investigated the association between the presence of LNM and the clinical and pathological factors of T2 CRC were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Certainty of evidence (CoE) was assessed using the GRADE approach., Results: Fourteen studies (8349 patients) were included. Overall, the proportion of LNM was 22%. The meta-analysis revealed that the presence of lymphovascular invasion (OR, 5.5; 95% CI 3.7-8.3; high CoE), high-grade tumor budding (OR, 2.4; 95% CI 1.5-3.7; moderate CoE), poor differentiation (OR, 2.2; 95% CI 1.8-2.7; moderate CoE), and female sex (OR, 1.3; 95% CI 1.1-1.7; high CoE) were associated with LNM in T2 CRC. Lymphatic invasion (OR, 5.0; 95% CI 3.3-7.6) was a stronger predictor of LNM than vascular invasion (OR, 2.4; 95% CI 2.1-2.8)., Conclusions: Lymphovascular invasion, high-grade tumor budding, poor differentiation, and female sex were risk factors for LNM in T2 CRC. Endoscopic resection of T2 CRC in patients with very low risk for LNM may become an alternative to conventional surgical resection., Trial Registration: PROSPERO, CRD42022316545., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC)., Methods: In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use., Results: We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use ( P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use ( P -trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period., Discussion: In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background & Aims: Emerging evidence implicates the importance of perinatal and early-life exposures in colorectal cancer (CRC) development. However, it remains unclear whether being breastfed in infancy is associated with CRC risk in adult life, particularly early adulthood., Methods: We prospectively investigated the association between history of being breastfed and risk of CRC and its precursor lesions among 66,634 women 46-93 years of age from the Nurses' Health Study and 92,062 women 27-68 years of age from the Nurses' Health Study II. Cox regression and logistic regression for clustered data were used to estimate hazard ratios for CRC and odds ratios for CRC precursors, respectively., Results: During 3.5 million person-years of follow-up, we identified 1490 incident cases of CRC in 2 cohorts. Having been breastfed was associated with a 23% (95% confidence interval [CI], 10% to 38%) increased risk of CRC. The risk of CRC increased with duration of being breastfed (P trend < .001). These findings were validated using breastfeeding information from the mothers of a subset of participants. Among younger participants from the Nurses' Health Study II, a significant association was observed between being breastfed and increased risk of high-risk adenomas under 50 years of age (odds ratio, 1.46; 95% CI, 1.16 to 1.83). Consistently, having been breastfed was associated with increased risk of CRC among participants ≤55 years of age (hazard ratio, 1.38; 95% CI, 1.06 to 1.80)., Conclusions: Being breastfed in infancy was associated with increased risk of CRC in adulthood, including among younger adults. However, further research is needed to understand the underlying biological mechanisms, as this association does not establish causation., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation and metabolic dysregulation are associated with increased risk of colorectal cancer (CRC); the underlying mechanisms are not fully understood. We characterized metabolomic signatures of inflammation and metabolic dysregulation and evaluated the association of the signatures and individual metabolites with CRC risk., Methods: Among 684 incident CRC cases and 684 age-matched controls in the Nurses' Health Study (n = 818 women) and Health Professionals Follow-up Study (n = 550 men), we applied reduced rank and elastic net regression to 277 metabolites for markers of inflammation (C-reactive protein, interleukin 6, tumor necrosis factor receptor superfamily member 1B, and growth differentiation factor 15) or metabolic dysregulation (body mass index, waist circumference, C-peptide, and adiponectin) to derive metabolomic signatures. We evaluated the association of the signatures and individual metabolites with CRC using multivariable conditional logistic regression. All statistical tests were 2-sided., Results: We derived a signature of 100 metabolites that explained 24% of variation in markers of inflammation and a signature of 73 metabolites that explained 27% of variation in markers of metabolic dysregulation. Among men, both signatures were associated with CRC (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.07 to 1.68 per 1-standard deviation increase, inflammation; OR = 1.25, 95% CI = 1.00 to 1.55 metabolic dysregulation); neither signature was associated with CRC in women. A total of 11 metabolites were individually associated with CRC and biomarkers of inflammation or metabolic dysregulation among either men or women., Conclusion: We derived metabolomic signatures and identified individual metabolites associated with inflammation, metabolic dysregulation, and CRC, highlighting several metabolites as promising candidates involved in the inflammatory and metabolic dysregulation pathways for CRC incidence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Complex diseases are often analyzed using disease subtypes classified by multiple biomarkers to study pathogenic heterogeneity. In such molecular pathological epidemiology research, we consider a weighted Cox proportional hazard model to evaluate the effect of exposures on various disease subtypes under competing-risk settings in the presence of partially or completely missing biomarkers. The asymptotic properties of the inverse and augmented inverse probability-weighted estimating equation methods are studied with a general pattern of missing data. Simulation studies have been conducted to demonstrate the double robustness of the estimators. For illustration, we applied this method to examine the association between pack-years of smoking before the age of 30 and the incidence of colorectal cancer subtypes defined by a combination of four tumor molecular biomarkers (statuses of microsatellite instability, CpG island methylator phenotype, BRAF mutation, and KRAS mutation) in the Nurses' Health Study cohort., (© 2024 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Background: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown., Methods: Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements., Results: During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-users, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (p nonlinearity < .001) and all-cause mortality (p nonlinearity  = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality., Conclusions: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality., (© 2024 American Cancer Society.)

Background: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC., Patients and Methods: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR., Results: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk., Conclusions: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Metformin, utilized to manage hyperglycemia, has been linked to a reduced risk of colorectal cancer (CRC) among individuals with diabetes. However, evidence is lacking for non-Hispanic Black individuals and those with lower socioeconomic status (SES), who face elevated risk for both diabetes and CRC. In this study, we investigated the association between metformin use and incident CRC risk within the Southern Community Cohort Study (SCCS), a racially- and SES-diverse prospective cohort., Methods: Participants reported their diabetes diagnosis and medications, including metformin, upon enrollment (2002-2009) and during follow-up surveys approximately every five years. Incident cases of CRC were identified through state cancer registries and the National Death Index. Proportional hazards models were employed to explore the relationship between metformin use and CRC risk, adjusted for cancer risk factors., Results: A total of 25,992 participants with diabetes were included in the analysis, among whom 10,095 were taking metformin. Of these participants, 76% identified as non-Hispanic Black, and 60% reported household incomes <$15,000/year. Metformin use was associated with a significantly lower CRC risk (HR [95% CI]: 0.71 [0.55-0.93]), with consistent results for both colon (0.80 [0.59-1.07]) and rectal cancers (0.49 [0.28-0.86]). The protective association appeared to be stronger among non-Hispanic White individuals (0.51 [0.31-0.85]) compared to non-Hispanic Black participants (0.80 [0.59-1.08], p-interaction =.13). Additionally, a protective association was observed among obese individuals (BMI ≥30 kg/m 2 , 0.59 [0.43-0.82] but not among non-obese participants (0.99 [0.65-1.51], p-interaction =.05) CONCLUSION: Our findings indicate that metformin use is associated with a reduced risk of CRC in individuals with diabetes, including among those from predominantly low SES backgrounds. These results support previous epidemiological findings, and demonstrate that the protective association for metformin in relation to incident CRC likely generalizes to populations with higher underlying risk., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk., Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated., Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10 -8 ). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10 -14 ); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10 -3 ), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk., Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use., (© 2024. The Author(s).)

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Objectives: Data support that enterotoxigenic Bacteroides fragilis (ETBF) harbouring the Bacteroides fragilis toxin (bft) gene may promote colorectal tumourigenesis through the serrated neoplasia pathway. We hypothesized that ETBF may be enriched in colorectal carcinoma subtypes with high-level CpG island methylator phenotype (CIMP-high), BRAF mutation, and high-level microsatellite instability (MSI-high)., Methods: Quantitative PCR assays were designed to quantify DNA amounts of Bacteroides fragilis, ETBF, and each bft gene isotype (bft-1, bft-2, or bft-3) in colorectal carcinomas in the Health Professionals Follow-up Study and Nurses' Health Study. We used multivariable-adjusted logistic regression models with the inverse probability weighting method., Results: We documented 4476 colorectal cancer cases, including 1232 cases with available bacterial data. High DNA amounts of Bacteroides fragilis and ETBF were positively associated with BRAF mutation (p ≤ 0.0003), CIMP-high (p ≤ 0.0002), and MSI-high (p < 0.0001 and p = 0.01, respectively). Multivariable-adjusted odds ratios (with 95% confidence interval) for high Bacteroides fragilis were 1.40 (1.06-1.85) for CIMP-high and 2.14 (1.65-2.77) for MSI-high, but 1.02 (0.78-1.35) for BRAF mutation. Multivariable-adjusted odds ratios for high ETBF were 2.00 (1.16-3.45) for CIMP-high and 2.86 (1.64-5.00) for BRAF mutation, but 1.09 (0.67-1.76) for MSI-high. Neither Bacteroides fragilis nor ETBF was associated with colorectal cancer-specific or overall survival., Discussion: The tissue abundance of Bacteroides fragilis is associated with CIMP-high and MSI-high, whereas ETBF abundance is associated with CIMP-high and BRAF mutation in colorectal carcinoma. Our findings support the aetiological relevance of Bacteroides fragilis and ETBF in the serrated neoplasia pathway., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective., Methods: Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification., Findings: During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01-1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03-1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (P interaction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM 2.5 exposure (per 10 μg/m 3 increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12-1.79; P = 0.004; I 2  = 90.8%). Genetically predicted methylation at PM 2.5 -related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO 2 -related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival., Interpretation: Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110., Funding: Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing., Methods: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia., Results: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women., Conclusions: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI., (© 2024. The Author(s).)

Objectives: Lymphovascular invasion (LVI) is a critical risk factor for lymph node metastasis (LNM), which requires additional surgery after endoscopic resection of T1 colorectal cancer (CRC). However, the impact of additional staining on estimating LNM is unclear. This systematic review aimed to evaluate the impact of additional staining on determining LNM in T1 CRC., Methods: We searched five electronic databases. Outcomes were diagnostic odds ratio (DOR), assessed using hierarchical summary receiver operating characteristic curves, and interobserver agreement among pathologists for positive LVI, assessed using Kappa coefficients (κ). We performed a subgroup analysis of studies that simultaneously included a multivariable analysis for other risk factors (deep submucosal invasion, poor differentiation, and tumor budding)., Results: Among the 64 studies (18,097 patients) identified, hematoxylin-eosin (HE) and additional staining for LVI had pooled sensitivities of 0.45 (95% confidence interval [CI] 0.32-0.58) and 0.68 (95% CI 0.44-0.86), specificities of 0.88 (95% CI 0.78-0.94) and 0.76 (95% CI 0.62-0.86), and DORs of 6.26 (95% CI 3.73-10.53) and 6.47 (95% CI 3.40-12.32) for determining LNM, respectively. In multivariable analysis, the DOR of additional staining for LNM (DOR 5.95; 95% CI 2.87-12.33) was higher than that of HE staining (DOR 1.89; 95% CI 1.13-3.16) (P = 0.01). Pooled κ values were 0.37 (95% CI 0.22-0.52) and 0.62 (95% CI 0.04-0.99) for HE and additional staining for LVI, respectively., Conclusion: Additional staining for LVI may increase the DOR for LNM and interobserver agreement for positive LVI among pathologists., (© 2023 The Authors. Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development., (© 2024. The Author(s).)

Objective: To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC)., Methods: Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA). Tumor infiltrating lymphocytes per high powered field (TILs/hpf) were scored by a gastrointestinal pathologist. Regression models were used to evaluate the associations between each variant and the three T-cell features, adjusting for sex, age, genotyping platform, and global ancestry. Three independent datasets were used for replication., Results: We identified a SNP (rs4918567) near RBM20 associated with clonality at a genome-wide significant threshold of 5 × 10 - 8 , with a consistent direction of association in both discovery and replication datasets. Expression quantitative trait (eQTL) analyses and in silico functional annotation for these loci provided insights into potential functional roles, including a statistically significant eQTL between the T allele at rs4918567 and higher expression of ADRA2A (P = 0.012) in healthy colon mucosa., Conclusions: Our study suggests that germline genetic variation is associated with the quantity and diversity of adaptive immune responses in CRC. Further studies are warranted to replicate these findings in additional samples and to investigate functional genomic mechanisms., (© 2024. The Author(s).)

Background: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC., Methods: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses., Results: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA., Conclusions: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88., Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases)., Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066)., Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available., Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival., (©2024 American Association for Cancer Research.)

Indoleamine 2,3-dioxygenase (IDO) and arginase-1 (ARG1) are amino acid-metabolizing enzymes, frequently highly expressed in cancer. Their expression may deplete essential amino acids, lead to immunosuppression, and promote cancer growth. Still, their expression patterns, prognostic significance, and spatial localization in the colorectal cancer microenvironment are incompletely understood. Using a custom 10-plex immunohistochemistry assay and supervised machine learning-based digital image analysis, we characterized IDO and ARG1 expression in monocytic cells, granulocytes, mast cells, and tumor cells in 833 colorectal cancer patients. We evaluated the prognostic value and spatial arrangement of IDO- and ARG1-expressing myeloid and tumor cells. IDO was mainly expressed not only by monocytic cells but also by some tumor cells, whereas ARG1 was predominantly expressed by granulocytes. Higher density of IDO + monocytic cells was an independent prognostic factor for improved cancer-specific survival both in the tumor center (P trend  = .0002; hazard ratio [HR] for the highest ordinal category Q4 [vs Q1], 0.51; 95% CI, 0.33-0.79) and the invasive margin (P trend  = .0015). Higher density of granulocytes was associated with prolonged cancer-specific survival in univariable models, and higher FCGR3 + ARG1 + neutrophil density in the tumor center also in multivariable analysis (P trend  = .0020). Granulocytes were, on average, located closer to tumor cells than monocytic cells. Furthermore, IDO + monocytic cells and ARG1 - granulocytes were closer than IDO - monocytic cells and ARG1 + granulocytes, respectively. The mRNA expression of the IDO1 gene was assessed in myeloid and tumor cells using publicly available single-cell RNA sequencing data for 62 colorectal cancers. IDO1 was mainly expressed in monocytes and dendritic cells, and high IDO1 activity in monocytes was associated with enriched immunostimulatory pathways. Our findings provided in-depth information about the infiltration patterns and prognostic value of cells expressing IDO and/or ARG1 in the colorectal cancer microenvironment, highlighting the significance of host immune response in tumor progression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The global prevalence of obesity and diabetes mellitus has increased in parallel with increasing cancer incidence, due to environmental and lifestyle factors and population aging. Metabolic diseases are associated with increased cancer risk, so a growing number of patients with cancer have coexistent obesity and/or diabetes mellitus. In this narrative review, we highlight recent evidence on the clinical impact of obesity and diabetes mellitus on the prognosis of prostate, breast, and colorectal cancer, and provide an overview of the underlying mechanisms. There is evidence that obesity is associated with increased risk of recurrence, and all-cause and cancer-specific mortality among adults with prostate, breast, and colorectal cancer. Diabetes mellitus is associated with increased all-cause and cancer-specific mortality for these 3 cancers, beyond any impact of obesity. Evidence also suggests increased risk of colorectal cancer recurrence in patients with diabetes mellitus. The underlying mechanisms are multifactorial and likely include hormonal imbalances and chronic inflammation that promote cancer cell growth. Obesity and diabetes mellitus are associated with increased risk of complications and side effects of cancer treatment. Associated comorbidities such as impaired kidney function, cardiovascular disease, and neuropathies may preclude the use of guideline cancer treatment and are competing causes of death. Cancer patients with metabolic diseases require a designated clinical program and a multidisciplinary approach involving oncologists, endocrinologists, surgeons, nutritionists, and physiotherapists, to ensure coordinated and optimized patient care., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis -variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPH's potential role in CRC prevention.

Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain., Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO)., Findings: A 1-standard deviation (SD:5.1 kg/m 2 ) increment in BMI levels was found to increase risks of Jass type 1 MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10 -5 ) and Jass type 2 non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4 non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3 non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10 -5 ) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03)., Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4)., Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements., Competing Interests: Declaration of interests AB has received a Scholar-in-Training Award from AACR for 2023. VM has received grants from Instituto de Salud Carlos III and FC AECC. BML has received support from Uppsala University as a part of a presentation in the Svedberg Seminar Series, and she was the president of the Australasian Epidemiological Association (2020–2023). BVG has received support grant from World Cancer Research Fund for a separate project within the same research field. AET has received an editorial board fee from NIH PDQ Cancer Genetics. MG has received research funding from Janssen and Servier, consulting fees from Nerviano Medical Sciences, Chromacode, and AstraZeneca and support to attend a meeting from Dava Oncology. JN has received research funding from Natera Inc and consulting fees from Leica Biosciences. MAJ has received an NIH funding. The remaining authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Treatment guidelines for colorectal cancer (CRC) suggest 2 classifications for histological differentiation-highest grade and predominant. However, the optimal predictor of lymph node metastasis (LNM) in T1 CRC remains unknown. This systematic review aimed to evaluate the impact of the use of highest-grade or predominant differentiation on LNM determination in T1 CRC., Methods: The study protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO, registration number: CRD42023416971) and was published in OSF ( https://osf.io/TMAUN/ ) on April 13, 2023. We searched 5 electronic databases for studies assessing the diagnostic accuracy of highest-grade or predominant differentiation to determine LNM in T1 CRC. The outcomes were sensitivity and specificity. We simulated 100 cases with T1 CRC, with an LNM incidence of 11.2%, to calculate the differences in false positives and negatives between the highest-grade and predominant differentiations using a bootstrap method., Results: In 42 studies involving 41,290 patients, the differentiation classification had a pooled sensitivity of 0.18 (95% confidence interval [CI] 0.13-0.24) and 0.06 (95% CI 0.04-0.09) ( P < 0.0001) and specificity of 0.95 (95% CI 0.93-0.96) and 0.98 (95% CI 0.97-0.99) ( P < 0.0001) for the highest-grade and predominant differentiations, respectively. In the simulation, the differences in false positives and negatives between the highest-grade and predominant differentiations were 3.0% (range 1.6-4.4) and -1.3% (range -2.0 to -0.7), respectively., Discussion: Highest-grade differentiation may reduce the risk of misclassifying cases with LNM as negative, whereas predominant differentiation may prevent unnecessary surgeries. Further studies should examine differentiation classification using other predictive factors., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Introduction: People with chronic conditions and people with colorectal cancer (CRC) may share common risk factors; thus, CRC screening is important for people with chronic conditions. We examined racial and ethnic differences in the use of CRC screening among people with various numbers of chronic conditions., Methods: We included data on adult respondents aged 50 to 75 years from the Behavioral Risk Factor Surveillance System in 2012 through 2020. We categorized counts of 9 conditions as 0, 1, 2, 3, and ≥4. We classified self-reported CRC screening status as up to date or not. We used Poisson models to estimate adjusted prevalence ratios (APRs) among the different counts of chronic conditions in 4 racial and ethnic groups: Hispanic adults with limited English proficiency (LEP), Hispanic adults without LEP, non-Hispanic Black adults, and non-Hispanic White adults., Results: Overall, 66.5% of respondents were up to date with CRC screening. The prevalence of being up to date increased with the number of chronic conditions. We found disparities among racial and ethnic groups. Hispanic respondents with LEP had lower rates than non-Hispanic White adults of being up to date with CRC screening across all counts of chronic conditions (APR for 0 conditions = 0.67; 95% CI, 0.64-0.71; APR for ≥4 conditions = 0.85; 95% CI, 0.79-0.91). Hispanic respondents without LEP with 0, 1, or 2 conditions were less likely than non-Hispanic White respondents to be up to date with CRC screening. We found no significant differences between non-Hispanic Black and non-Hispanic White respondents., Conclusion: We found disparities among Hispanic BRFSS respondents with LEP, who had lower rates than non-Hispanic White respondents of being up to date with CRC screening, regardless of the number of chronic conditions. Tailored interventions are needed to address these disparities and improve screening rates, particularly among Hispanic people.

Background: While tall stature has been linked to an increase in the risk of colorectal cancer (CRC), its association with cancer in the colorectum and its subsites remains unclear among Asians., Methods: We conducted a pooled analysis of 10 population-based cohort studies among adults in Japan. Each study estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC incidence associated with adult height were estimated using Cox proportional hazards regression with adjustment of the same set of covariates were then pooled to estimate summary HRs incidence using random-effect models., Results: We identified 9,470 CRC incidences among 390,063 participants during 5,672,930 person-years of follow-up. Men and women with tall stature had a higher risk of CRC and colon cancer. HRs for CRC, colon cancer, and distal colon cancer for the highest versus lowest height categories were 1.23 (95% CI, 1.07-1.40), 1.22 (95% CI, 1.09-1.36), and 1.27 (95% CI, 1.08-1.49), respectively, in men and 1.21 (95% CI, 1.09-1.35), 1.23 (95% CI, 1.08-1.40), and 1.35 (95% CI, 1.003-1.81), respectively, in women. The association with proximal colon cancer and rectal cancer was less evident in both sexes., Conclusion: This pooled analysis confirms the link between tall stature and a higher risk of CRC and colon cancer (especially distal colon) among the Japanese and adds evidence to support the use of adult height to identify those at a higher risk of CRC.

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Colorectal cancer (CRC) risk is associated with modifiable lifestyle factors including smoking, physical inactivity, Western diet, and excess body weight. The impact of lifestyle factors on survival is less known. A cohort study was conducted to investigate the combined effects of a healthy lifestyle and body mass index on prognosis following CRC diagnosis., Methods: Treatment and follow-up data were collected from the patient files of 1098 participants from the Colorectal cancer low-risk study cohort including stage I-III CRC patients. A healthy lifestyle and BMI (HL) score was computed using self-reported data on smoking status, physical activity, adherence to a Mediterranean diet pattern, and BMI, and divided into four categories ranging from least to most healthy. Survival analyses were performed to assess recurrence-free survival and overall survival across categories of exposure, using the Kaplan-Meier method and Cox proportional hazards models adjusted for age, sex, and educational level., Results: Among 1098 participants with stage I-III CRC, 233 (21.2%) had an HL score of 0-1 (least healthy), 354 (32.2%) HL score of 2, 357 (32.5%) HL score of 3 and 154 (14.0) HL score 4 (most healthy). Patients with the healthiest lifestyle (HL score 4) compared to the least healthy (HL score 0-1) had an improved recurrence-free survival (HL 4 vs HL 0-1, HRadj 0.51 (95% CI 0.31-0.83) and overall survival (HL 4 vs HL 0-1, HRadj 0.52 (95% CI 0.38-0.70)., Conclusion: Adherence to a healthy lifestyle may increase the recurrence-free and overall survival of patients with stage I-III CRC., (© 2023. The Author(s).)

Background: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations., Methods: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines., Results: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166., Conclusion: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death., Methods: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses., Results: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test., Conclusions: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to understand how an interactive, web-based simulation tool can be optimized to support decision-making about the implementation of evidence-based interventions (EBIs) for improving colorectal cancer (CRC) screening., Methods: Interviews were conducted with decision-makers, including health administrators, advocates, and researchers, with a strong foundation in CRC prevention. Following a demonstration of the microsimulation modeling tool, participants reflected on the tool's potential impact for informing the selection and implementation of strategies for improving CRC screening and outcomes. The interviews assessed participants' preferences regarding the tool's design and content, comprehension of the model results, and recommendations for improving the tool., Results: Seventeen decision-makers completed interviews. Themes regarding the tool's utility included building a case for EBI implementation, selecting EBIs to adopt, setting implementation goals, and understanding the evidence base. Reported barriers to guiding EBI implementation included the tool being too research-focused, contextual differences between the simulated and local contexts, and lack of specificity regarding the design of simulated EBIs. Recommendations to address these challenges included making the data more actionable, allowing users to enter their own model inputs, and providing a how-to guide for implementing the simulated EBIs., Conclusion: Diverse decision-makers found the simulation tool to be most useful for supporting early implementation phases, especially deciding which EBI(s) to implement. To increase the tool's utility, providing detailed guidance on how to implement the selected EBIs, and the extent to which users can expect similar CRC screening gains in their contexts, should be prioritized., (© 2023. The Author(s).)

Purpose: To assess preferences for design of a pharmacy-based colorectal cancer (CRC) screening program (PharmFIT™) among screening-eligible adults in the United States (US) and explore the impact of rurality on pharmacy use patterns (e.g., pharmacy type, prescription pick-up preference, service quality rating)., Methods: We conducted a national online survey of non-institutionalized US adults through panels managed by Qualtrics, a survey research company. A total of 1,045 adults (response rate 62%) completed the survey between March and April 2021. Sampling quotas matched respondents to the 2010 US Census and oversampled rural residents. We assessed pharmacy use patterns by rurality and design preferences for learning about PharmFIT™; receiving a FIT kit from a pharmacy; and completing and returning the FIT kit., Results: Pharmacy use patterns varied, with some notable differences across rurality. Rural respondents used local, independently owned pharmacies more than non-rural respondents (20.4%, 6.3%, p < 0.001) and rated pharmacy service quality higher than non-rural respondents. Non-rural respondents preferred digital communication to learn about PharmFIT™ (36% vs 47%; p < 0.001) as well as digital FIT counseling (41% vs 49%; p = 0.02) more frequently than rural participants. Preferences for receiving and returning FITs were associated with pharmacy use patterns: respondents who pick up prescriptions in-person preferred to get their FIT (OR 7.7; 5.3-11.2) and return it in-person at the pharmacy (OR 1.7; 1.1-2.4)., Conclusion: Pharmacies are highly accessible and could be useful for expanding access to CRC screening services. Local context and pharmacy use patterns should be considered in the design and implementation of PharmFIT™., (© 2023. The Author(s).)

Importance: Type 2 diabetes and colorectal cancer (CRC) disproportionately burden indviduals of low socioeconomic status and African American race. Although diabetes is an emerging CRC risk factor, associations between diabetes and CRC in these populations are understudied., Objective: To determine if diabetes is associated with CRC risk in a cohort representing understudied populations., Design, Setting, and Participants: This cohort study uses data from the prospective Southern Community Cohort Study in the US, which recruited from 2002 to 2009 and completed 3 follow-up surveys by 2018. Of about 85 000 participants, 86% enrolled at community health centers, while 14% were enrolled via mail or telephone from the same 12 recruitment states. Participants with less than 2 years of follow-up, previous cancer diagnosis (excluding nonmelanoma skin cancer) at enrollment, missing enrollment diabetes status, diabetes diagnosis before age 30, and without diabetes at enrollment with no follow-up participation were excluded. Data were analyzed from January to September 2023., Exposures: Physician-diagnosed diabetes and age at diabetes diagnosis were self-reported via survey at enrollment and 3 follow-ups., Main Outcomes and Measures: Diabetes diagnosis was hypothesized to be positively associated with CRC risk before analysis. Incident CRC was assessed via state cancer registry and National Death Index linkage. Hazard ratios and 95% CIs were obtained via Cox proportional hazard models, using time-varying diabetes exposure., Results: Among 54 597 participants, the median (IQR) enrollment age was 51 (46-58) years, 34 786 (64%) were female, 36 170 (66%) were African American, and 28 792 (53%) had income less than $15 000 per year. In total, 289 of 25 992 participants with diabetes developed CRC, vs 197 of 28 605 participants without diabetes. Diabetes was associated with increased CRC risk (hazard ratio [HR], 1.47; 95% CI, 1.21-1.79). Greater associations were observed among participants without colonoscopy screening (HR, 2.07; 95% CI, 1.16-3.67) and with smoking history (HR, 1.62; 95% CI, 1.14-2.31), potentially due to cancer screening differences. Greater associations were also observed for participants with recent diabetes diagnoses (diabetes duration <5 years compared with 5-10 years; HR, 2.55; 95% CI, 1.77-3.67), possibly due to recent screening., Conclusions and Relevance: In this study where the majority of participants were African American with low socioeconomic status, diabetes was associated with elevated CRC risk, suggesting that diabetes prevention and control may reduce CRC disparities. The association was attenuated for those who completed colonoscopies, highlighting how adverse effects of diabetes-related metabolic dysregulation may be disrupted by preventative screening.

Background: The associations of vitamin C intake with colorectal cancer (CRC) survival according to tumour KRAS or BRAF mutation status remain unclear., Methods: We used the inverse probability weighted multivariable Cox proportional hazards regression model to calculate the hazard ratio (HR) of mortality, and spline analysis to evaluate the dose-response relationship in the Nurses' Health Study and Health Professionals Follow-up Study. We also assessed SLC2A1 mRNA expression according to KRAS or BRAF mutation in the TCGA database., Results: During an average of 12.0 years of follow-up, we documented 2,096 CRC cases, of which 703 cases had KRAS and BRAF mutation data. The association between total vitamin C intake and CRC-specific mortality suggestively differed according to KRAS or BRAF mutation status (P interaction  = 0.04), with the multivariable HR (95% CI) per 400 mg/day increase in vitamin C intake for CRC-specific mortality of 1.07 (0.87-1.32, P trend  = 0.52) in cases with both wild type and 0.74 (0.55-1.00, P trend  < 0.05) in cases with either KRAS or BRAF mutant type. TCGA analysis showed a higher mRNA SLC2A1 expression in KRAS or BRAF-mutated tumours than in wild-type tumours (P = 0.02)., Conclusion: Our findings support the laboratory evidence for a potential benefit of vitamin C for CRC patients with KRAS or BRAF mutated tumours., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Early-onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early-life factors and EOCRC risk, with a particular focus on long-term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC-related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early-onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early-life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early-onset CRC (OR = 1.48, 95% CI = 1.01-2.17, P = .046) and adenomas (OR = 1.40, 95% CI = 1.17-1.68, P < .001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early-onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79-1.52, P = .587, for CC genotype; OR = 1.75, 95% CI = 1.16-2.64, P = .008, for TT genotype; P interaction  = .089). Our study suggested that LRAU during early life is associated with increased risk of early-onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome-related pathway underlying colorectal carcinogenesis, are warranted., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice., (© 2023. Springer Nature Limited.)

Background: The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC)., Methods: Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets., Results: Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC., Conclusions: This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Evidence concerning intakes of protein or sources of dairy protein and risks of colorectal, breast, and prostate cancers is inconclusive., Methods: Using a subsample of UK Biobank participants who completed ≥2 (maximum of 5) 24-h dietary assessments, we estimated intakes of total protein, protein from total dairy products, milk, and cheese, and dietary calcium in 114,217 participants. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using multivariable-adjusted Cox regression., Results: After a median of 9.4 years of follow-up, 1193 colorectal, 2024 female breast, and 2422 prostate cancer cases were identified. There were inverse associations of total dairy protein, protein from milk, and dietary calcium intakes with colorectal cancer incidence (HR Q4 vs Q1 :0.80, 95% CI: 0.67-0.94; 0.79, 0.67-0.94; 0.71, 0.58-0.86, respectively). We also observed positive associations of milk protein and dietary calcium with prostate cancer risk (HR Q4 vs Q1 :1.12, 1.00-1.26 and 1.16, 1.01-1.33, respectively). No significant associations were observed between intake of dairy protein and breast cancer risk. When insulin-like growth factor-I concentrations measured at recruitment were added to the multivariable-adjusted models, associations remained largely unchanged. Analyses were also similar when looking at total grams of dairy products, milk, and cheese., Conclusion: Further research is needed to understand the mechanisms underlying the relationships of dairy products with cancer risk and the potential roles of dietary protein and calcium., (© 2023. The Author(s).)

Background: Colorectal cancer is one of the leading cancers worldwide and in Vietnam. Adenomas are important precursors of colorectal cancer. Study on the association between sleep duration and development of colorectal adenoma (CRA) is limited, particularly among Vietnamese population., Methods: We conducted an individually matched case-control study of 870 CRA cases and 870 controls in a large-scale colorectal screening program involving 103,542 individuals ages ≥40 years old in Hanoi, Vietnam. Sleep duration was categorized in three groups: short: ≤6 hours/day, normal: 7 to 8 hours/day, and long: >8 hours/day. Conditional logistic regression was used to evaluate the association between sleep duration and adenomas risk after controlling for potential confounders., Results: Overall, short-sleep duration was associated with increased risk of having CRA compared with normal duration [OR, 1.48; 95% confidence interval (CI), 1.12-1.97]. This pattern was present in both females (OR, 1.58; 95% CI, 1.14-2.18) and males (OR, 1.45; 95% CI, 1.08-1.93), with advanced adenomas (OR, 1.61; 95% CI, 1.09-2.38) and non-advanced adenomas (OR, 1.66; 95% CI, 1.19-2.32). Furthermore, the association between CRA development and short-sleep duration was more apparent among females who were nondrinker, nonobese, physically active, with proximal or both sided adenomas and with cardiometabolic disorder. Among males, the short-sleep duration was associated with CRA risk among never-smoking, cardiometabolic disorders, and obese., Conclusions: Short-sleep duration was associated with increased prevalence of both advanced and non-advanced CRAs among Vietnamese population., Impact: Findings from this study showed that maintaining an adequate sleep duration may have an important implication for colorectal adenoma prevention and control., (©2023 American Association for Cancer Research.)

Background: The United States Preventive Services Task Force (USPSTF) lists 32 grade A or B recommended preventive services for non-pregnant United States (US) adults, including colorectal cancer screening (CRC). Little guidance is given on how to implement these services with consistency and fidelity in primary care. Given limited patient visit time and competing demands, primary care providers (PCPs) tend to prioritize a small subset of these recommendations. Completion rates of some of these services, including CRC screening, are suboptimal. Expanding delivery of preventive services to other healthcare providers, where possible, can improve access and uptake, particularly in medically underserved areas or populations. Fecal immunochemical testing (FIT) (at-home, stool-based testing) for CRC screening can be distributed and resulted without PCP involvement. Pharmacists have long delivered preventive services (e.g., influenza vaccination) and may be a good option for expanding CRC screening delivery using FIT, but it is not clear how PCPs would perceive this expansion., Methods: We used semi-structured interviews with PCPs in North Carolina and Washington state to assess perceptions and recommendations for a potential pharmacy-based FIT distribution program (PharmFIT™). Transcripts were coded and analyzed using a hybrid inductive-deductive content analysis guided by the Consolidated Framework for Implementation Research (CFIR) to elucidate potential multi-level facilitators of and barriers to implementation of PharmFIT™., Results: We completed 30 interviews with PCPs in North Carolina (N = 12) and Washington state (N = 18). PCPs in both states were largely accepting of PharmFIT™, with several important considerations. First, PCPs felt that pharmacists should receive appropriate training for identifying patients eligible and due for FIT screening. Second, a clear understanding of responsibility for tracking tests, communication, and, particularly, follow-up of positive test results should be established and followed. Finally, clear electronic workflows should be established for relay of test result information between the pharmacy and the primary care clinic., Conclusion: If the conditions are met regarding pharmacist training, follow-up for positive FITs, and transfer of documentation, PCPs are likely to support PharmFIT™ as a way for their patients to obtain and complete CRC screening using FIT., (© 2023. BioMed Central Ltd., part of Springer Nature.)