Incident Colorectal Cancer Cases Research Articles

Novel metabolomic predictors of incident colorectal cancer in men and women.

Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed pre-diagnostic metabolome-wide analyses with CRC risk. We conducted a nested case-control study among women (Nurses' Health Study (NHS)) and men (Health Professionals Follow-up Study (HPFS)) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 NHS, 275 HPFS) incident CRC cases occurred and were matched 1:1 to controls. Liquid chromatography-mass spectrometry (LC-MS) identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis (MSEA) was used to identify differential abundance in metabolite classes. Weighted Correlation Network Analysis (WGCNA) provided modules of covarying metabolites, which were tested for CRC association. MSEA identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC cases diagnosed two years after blood draw, myristoleic acid (OR = 1.37; 95%CI = 1.15-1.62; FDR = 0.072) and C60:12 triacylglycerol (OR = 0.75; 95%CI = 0.64-0.88; FDR = 0.072 were associated with CRC risk in women. WGCNA identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women. We identified pre-diagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies.

Serum bilirubin levels and risk of colorectal cancer in Korean adults: results from the Korean Genome and Epidemiology Study-Health Examinee (KoGES-HEXA) Cohort Study.

Current evidence on associations between circulating bilirubin and colorectal cancer (CRC) risk is inconsistent. In this prospective study, we investigated associations of pre-diagnostic circulating levels of total and indirect bilirubin with CRC risk in 78,467 Korean adults aged 40-78 years at recruitment, considering potential non-linearity and sex differences. Hazard ratios (HR) and 95% confidence intervals (CI) for associations with CRC risk were estimated with Cox proportional hazard regression. During a median 7.9-year follow-up, 539 incident CRC cases were recorded. In multivariable-adjusted models, higher levels of total bilirubin were associated with a 26% (CI: 42% to 7%) lower risk of CRC among men and women combined, comparing the highest with the lowest tertile (P-linear trend = 0.003). A U-shaped association was observed in men, with the lowest risk at approximately 0.8 mg/dL (=13.7 μmol/L) of total bilirubin (P for non-linearity = 0.01). Although the association was largely null in women, there was no evidence for effect modification by sex (P-interaction = 0.73). Associations between indirect bilirubin and CRC risk were similar. Higher circulating levels of total and indirect bilirubin were inversely associated with the risk of CRC among Korean adults. The associations were strongly inverse and U-shaped among men.

Evaluation of long-term benefits and cost-effectiveness of nation-wide colorectal cancer screening strategies in China in 2020–2060: a modelling analysis

Evidence on the long-term benefits and cost-effectiveness of colorectal cancer (CRC) screening strategies in China remains limited. This modelling study aims to address this issue for various CRC screening strategies in China between 2020 and2060. Using a previously developed microsimulation model (MIMIC-CRC) with Chinese epidemiological data, we evaluated four CRC screening strategies targeting population aged 45-74 years: no screening, colonoscopy every 10years, biennial faecal immunochemical testing (FIT), and a roll-out FIT screening strategy. Screening coverage (invitation) rates from 5% to 100% were analysed. Single-cohort analysis of 100,000 individuals was conducted to estimate the relative cost-effectiveness of each strategy. A multiple-cohort analysis of 100,000 people aged 40+ over 2020-2060 was conducted to project nation-wide long-term benefits and cost-effectiveness. In single-cohort analysis, all strategies yielded reductions in CRC incidence and mortality compared to no screening, with colonoscopy outperforming FIT-based strategies at the same invitation rates. In multiple-cohort analysis, among people over 40 years of age in China over 2020-2060, compared to no screening, at invitation rate of 5%, screening by colonoscopy, biennial FIT and roll-out FIT-based approach were estimated to avert 1.2, 0.4, and 0.3 million incident CRCs and 0.2, 0.1, and 0.1 million CRC-related deaths, respectively, compared to no screening (25.4 million incident CRCs and 4.4 million CRC-related deaths), and this preventive effect enlarged as the screening coverage rate increased. At full coverage, colonoscopy achieved the largest reductions (38.2% lower incidence and 43.2% lower mortality) but required the most resources. Biennial FIT and roll-out FIT-based approach screening was slightly less effective but had significant reduced colonoscopy needs (reduction of 83.8% and 85.2%, respectively) and overall cost (reduction of 23.4% and 37.8%, respectively) compared to colonoscopy screening. Nation-wide implementation of screening would be effective in reducing the burden of CRC in China. Biennial FIT and roll-out FIT-based screening strategies could prevent incident CRC cases and CRC-related deaths with considerably fewer resources than colonoscopy screening. Efforts should be made to increase the screening coverage in China. Chinese Academy of Medical Science Innovation Fund for Medical Science (2022-I2M-1-0031); National Natural Science Foundation of China (82173606; 82273726); Beijing Nova Program of Science and Technology (20230484397).

Abstract A048: Association between ambient particulate matter and colorectal cancer incidence: The Multiethnic Cohort Study

Abstract Background: Growing evidence suggests that air pollution may be a risk factor for colorectal cancer (CRC). We examined the association between ambient particulate matter (PM) exposure and CRC risk within the Multiethnic Cohort Study (MEC), representing the first study to include a large sample of racial and ethnic minoritized populations. Methods: The MEC is a prospective study that recruited, from 1993 through 1996, men and women ages 45-75 years largely from five racial and ethnic groups (African American, Japanese American, Latino, Native Hawaiian, and Non-Hispanic White) living in Hawai‘i and California. This study included 98,675 California MEC participants, residing predominately in Los Angeles County. Satellite-based PM2.5 (PM with an aerodynamic diameter <2.5μm) exposures were estimated from a published spatiotemporal model. Kriging interpolation was used to estimate PM10 (PM <10μm) exposures using routine air monitoring data from the US Environmental Protection Agency. Time-varying PM exposures were assessed from time of recruitment through 12/31/2018. Incident invasive CRC cases were identified via linkage with the California Cancer Registry (n=3,217). Cox proportional hazards models were used to examine the association between PM and CRC risk using age as the time metric, with strata defined by age at cohort entry and race and ethnicity, and adjusting for demographic and lifestyle factors. Heterogeneity of the PM-CRC association was assessed by sex, race and ethnicity, and CRC subsite (right colon, left colon, rectum). Results: Risk of CRC increased with PM2.5 (per 10μg/m3 hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.96-1.33) with a larger HR observed among females (HR 1.29, 95% CI 1.03-1.62) than males (HR 0.96, 95% CI 0.76-1.22) (Pheterogeneity=0.24). CRC risk was positively associated with PM2.5 across race and ethnicity (except for African American participants) with the largest HR observed among Latino participants (HR 1.47, 95% CI 1.03-2.08) (Pheterogeneity=0.20). There was no statistically significant heterogeneity of PM2.5 effect by tumor subsite (Pheterogeneity=0.07); although larger HRs were seen for left colon (HR 1.52, 95% CI 1.08- 2.14) and rectal cancers (HR 1.54, 95% CI 1.05-2.25) than right colon cancers (HR 1.09, 95% CI 0.88-1.35). PM10 was not associated with CRC risk (per 10 μg/m3; HR 1.02, 95% CI 0.93-1.22) with no evidence of heterogeneity in associations by sex or race and ethnicity (respective Pheterogeneity 0.75, 0.44). Although HRs for PM10 appeared to differ by CRC subsite (Pheterogeneity=0.03), the 95% CI of these HRs included the null (right HR 0.95, 95% CI 0.84-1.06; left HR 1.13, 95% CI 0.95-1.35; rectal HR 1.18, 95% CI 0.97-1.43). Conclusions: Preliminary findings suggest that PM2.5 exposure is associated with CRC risk with larger associations in females and, possibly, for left colon and rectal cancer. Additional studies are needed to confirm these findings and evaluate the potential biological pathways underlying these associations. Citation Format: Ugonna Ihenacho, Chiuchen Tseng, Jun Wu, Scott Fruin, Timothy V. Larson, Salma Shariff-Marco, Loïc Le Marchand, Daniel O. Stram, Lynne R. Wilkens, Christopher A. Haiman, Beate Ritz, Iona Cheng, Anna H. Wu. Association between ambient particulate matter and colorectal cancer incidence: The Multiethnic Cohort Study [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A048.

An Empirical Dietary Pattern Associated With the Gut Microbial Features in Relation to Colorectal Cancer Risk

Background & AimsEpidemiologic evidence for dietary influence on colorectal cancer (CRC) risk through the gut microbiome remains limited. MethodsLeveraging 307 men and 212 women with stool metagenomes and dietary data, we characterized and validated a sex-specific dietary pattern associated with the CRC-related gut microbial signature (CRC Microbial Dietary Score [CMDS]). We evaluated the associations of CMDS with CRC risk according to Fusobacterium nucleatum, pks+Escherichia coli, and enterotoxigenic Bacteroides fragilis (ETBF) status in tumor tissue using Cox proportional hazards regression in the Health Professionals Follow-up Study (1986-2018), Nurses’ Health Study (NHS) (1984-2020), and NHS II (1991-2019). ResultsThe CMDS was characterized by high industrially processed foods and low unprocessed fiber-rich foods intakes. In 259,200 participants, we documented 3,854 incident CRC cases over 6,467,378 person-years of follow-up. CMDS was associated with a higher risk of CRC (Ptrend<0.001), with a multivariable hazard ratio (HRQ5vs.Q1) of 1.25 (95%CI, 1.13-1.39). The association remained after adjusting for previously established dietary patterns, e.g., the Western and prudent diets. Notably, the association was stronger for tumoral F. nucleatum-positive (HRQ5vs.Q1, 2.51; 95%CI, 1.68-3.75; Ptrend<0.001) (Pheterogeneity=0.03, positivity vs. negativity), pks+E. coli-positive (HRQ5vs.Q1, 1.68; 95%CI, 0.84-3.38; Ptrend=0.005) (Pheterogeneity=0.01, positivity vs. negativity), and ETBF-positive CRC (HRQ5vs.Q1, 2.06; 95%CI, 1.10-3.88; Ptrend=0.016) (Pheterogeneity=0.06, positivity vs. negativity), compared with their negative counterparts. ConclusionsCMDS was associated with increased CRC risk, especially for tumors with detectable F. nucleatum, pks+E. coli, and ETBF in tissue. Our findings support a potential role of the gut microbiome underlying the dietary effects on CRC.

Body Mass Index and Risk of Colorectal Cancer Incidence and Mortality in Asia

The global burden of obesity is increasing, as are colorectal cancer (CRC) incidence and mortality. To assess the association between body mass index (BMI) and risks of incident CRC and CRC-related death in the Asian population. 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. Body mass index, calculated as weight in kilograms divided by height in meters squared. 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. 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). 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.

Intake of Sugar and Food Sources of Sugar and Colorectal Cancer Risk in the Multiethnic Cohort Study

BackgroundThe influence of sugar intake on the risk of colorectal cancer (CRC) remains controversial, and there is a need to investigate the heterogeneity of effects among racial and ethnic groups. ObjectivesTo examine the association of intake of simple sugars and their food sources with CRC risk according to race/ethnicity in a multiethnic cohort study. MethodsWe analyzed data from 192,651 participants who participated in the Multiethnic Cohort Study comprising African American, Japanese American, Latino, Native Hawaiian, and White older adults living in Hawaii and California with an average follow-up of 19 y. Intakes of total and specific types of sugars and sugary foods were estimated from a quantitative food frequency questionnaire completed by the participants in 1993–1996. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC risk according to quintiles (Q) of sugar and food intakes using Cox models adjusted for potential confounders. ResultsAs of December 2017, 4403 incident CRC cases were identified. Among all participants, multivariable-adjusted CRC HRs for Q2, Q3, Q4, and Q5 compared with Q1 for total sugars were 1.03 (95% CI: 0.94, 1.13), 1.05 (95% CI: 0.96, 1.16), 1.12 (95% CI: 1.01, 1.24), and 1.13 (95% CI: 1.01, 1.27), respectively. A similar positive association was observed for total fructose, glucose, fructose, and maltose but not for added sugars and sugary foods. The increased risk appeared to be limited to colon cancer and to be strongest among younger participants (i.e., 45–54 y at baseline); an association with CRC was observed for sugar-sweetened beverages in the latter group. Among racial and ethnic groups, increased risk of CRC was most apparent in Latinos. ConclusionsIn this diverse cohort, intakes of total sugar, total fructose, glucose, fructose, and maltose were associated with an increased risk of CRC, and the association was strongest for colon cancer, younger participants, and Latinos.

Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status.

To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum, bacterial species implicated in colorectal carcinogenesis. The absence of the appendix, an immune system organ and a possible reservoir of certain pathogenic microbes, may affect the intestinal microbiome, thereby altering long-term colorectal cancer risk. Utilizing databases of prospective cohort studies, namely the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of appendectomy history with colorectal cancer incidence overall and subclassified by the amount of tumor tissue Fusobacterium nucleatum​​ (Fusobacterium animalis). We used an inverse probability weighted multivariable-adjusted duplication-method Cox proportional hazards regression model. During the follow-up of 139,406 participants (2,894,060 person-years), we documented 2811 incident colorectal cancer cases, of which 1065 cases provided tissue F. nucleatum analysis data. The multivariable-adjusted hazard ratio of appendectomy for overall colorectal cancer incidence was 0.92 (95% CI, 0.84-1.01). Appendectomy was associated with lower F. nucleatum-positive cancer incidence (multivariable-adjusted hazard ratio, 0.53; 95% CI, 0.33-0.85; P=0.0079), but not F. nucleatum-negative cancer incidence (multivariable-adjusted hazard ratio, 0.98; 95% CI, 0.83-1.14), suggesting a differential association by F. nucleatum status (Pheterogeneity=0.015). This differential association appeared to persist in various participant/patient strata including tumor location and microsatellite instability status. Appendectomy likely lowers the future long-term incidence of F. nucleatum-positive (but not F. nucleatum-negative) colorectal cancer. Our findings do not support the existing hypothesis that appendectomy may increase colorectal cancer risk.

Blood-Based Epigenetic Age Acceleration and Incident Colorectal Cancer Risk: Findings from a Population-Based Case-Control Study.

This study investigates the association between epigenetic age acceleration (EAA) derived from DNA methylation and the risk of incident colorectal cancer (CRC). We utilized data from a random population sample of 9,360 individuals (men and women, aged 45-69) from the HAPIEE Study who had been followed up for 16 years. A nested case-control design yielded 35 incident CRC cases and 354 matched controls. Six baseline epigenetic age (EA) measures (Horvath, Hannum, PhenoAge, Skin and Blood (SB), BLUP, and Elastic Net (EN)) were calculated along with their respective EAAs. After adjustment, the odds ratios (ORs) for CRC risk per decile increase in EAA ranged from 1.20 (95% CI: 1.04-1.39) to 1.44 (95% CI: 1.21-1.76) for the Horvath, Hannum, PhenoAge, and BLUP measures. Conversely, the SB and EN EAA measures showed borderline inverse associations with ORs of 0.86-0.87 (95% CI: 0.76-0.99). Tertile analysis reinforced a positive association between CRC risk and four EAA measures (Horvath, Hannum, PhenoAge, and BLUP) and a modest inverse relationship with EN EAA. Our findings from a prospective population-based-case-control study indicate a direct association between incident CRC and four markers of accelerated baseline epigenetic age. In contrast, two markers showed a negative association or no association. These results warrant further exploration in larger cohorts and may have implications for CRC risk assessment and prevention.

The underestimated preventive effects of flexible sigmoidoscopy screening: re-analysis and meta-analysis of randomized trials

Flexible sigmoidoscopy (FS), which is less invasive, resource intensive and costly than colonoscopy, is among the recommended screening options for colorectal cancer (CRC). Four large randomized trials consistently reported statistically significant, albeit modest effects of screening by FS on CRC incidence. However, their effect estimates included cancers that were already prevalent at recruitment and could not have been prevented by screening. We performed a re-analysis and meta-analysis of two of the trials (including the largest one) to estimate reduction of truly incident cases by a single FS offered between 55 and 64 years of age among the “at risk study population” without prevalent CRC at recruitment. In meta-analyses of data reported after more than 15 years of follow-up, relative risk (95% CI) in intention-to-screen and per-protocol analyses were 0.71 (0.66–0.76) and 0.59 (0.55–0.65) for any CRC, and 0.52 (0.47–0.57) and 0.34 (0.30–0.39) for distal CRC, respectively. These results indicate much stronger effects than those suggested by the original reports and imply that a single screening FS can prevent approximately two out of three distal incident CRC cases within 15 + years of follow-up.

Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study

This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. 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. 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 (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10μg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI= 1.12-1.79; P=0.004; I2=90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-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. 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. 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).

Abstract 2197: Weight history and colorectal cancer risk in the Cancer Prevention Study-3 cohort

Abstract While the link between obesity and colorectal carcinogenesis is established, limited evidence suggests that early-life overweight/obesity may be an important consideration, particularly in the development of early-onset colorectal cancer (CRC). Using data from the American Cancer Society’s Cancer Prevention Study-3 (CPS-3), we investigated the association of body weight across the life course and risk of CRC. From 2006-13, over 300,000 participants (ages 30-65) enrolled in the CPS-3 cohort and provided a baseline waist circumference (WC) measure, self-reported baseline weight and height, weight at age 18, and weight at each decade of adulthood (20s to current age). Body shape phenotype (apple, pear, other) was self-reported in 2015. Excess body mass index (BMI)-years was calculated by subtracting a reference BMI of 25 from the reported BMI for each decade of life and aggregating excess BMI for the reported years of life. Through 2018, 424 incident cases of colorectal cancer were reported, of which 94 were younger than 50 years. Associations of BMI measures and WC with incident CRC were estimated using multivariable-adjusted Cox proportional hazards regression and stratified by sex and body shape. After exclusions (n=248,804), 78% of participants were women, 85% were non-Hispanic white, 69% were never smokers, and 8% had a family history of CRC. The mean baseline age was 47.8 (women) and 48.5 (men) years. The mean baseline BMI, WC, and age 18 BMI were 27.6 kg/m2, 91.9 cm, and 21.7 kg/m2, respectively, among women and 28.3 kg/m2, 103.8 cm, and 23.1 kg/m2, respectively, among men. Baseline BMI was associated with 8% higher CRC risk (95% confidence interval (CI) 0.99-1.18) per 5 kg/m2 increase. However, apple body shape was associated with higher CRC risk (hazard ratio (HR) per 5 kg/m2 BMI = 1.18, 95% CI 1.02-1.38). WC was associated with higher CRC risk (HR 1.08, 95% CI 1.01-1.15) per 10 cm increase, and the association was higher for apple body shape (HR 1.14, 95% CI 1.01-1.28). BMI at age 18 was associated with 17% higher CRC risk (95% CI 1.03-1.32) per 5 kg/m2 increase, and the association was higher for apple body shape (HR 1.36, 95% CI 1.12-1.65). Associations for non-apple body shapes were not statistically significant across all exposures. For early-onset CRC, associations with baseline BMI, WC, and age 18 BMI were suggestive of higher risk but not statistically significant. Participants in the highest category of excess BMI-years (women ≥35, men ≥81) relative to those in the lowest had 56% higher risk of overall CRC (95% CI 1.19-2.05), but the association with early-onset CRC was not statistically significant (HR 1.92, 95% CI 0.90-4.07). These findings suggest that while obesity is associated with higher CRC risk, excess weight gain around the waist and at younger ages may be of importance. Studies are needed to confirm these findings and further investigate the potential role of early-life obesity in the development of early-onset CRC. Citation Format: Caroline Y. Um, Christina C. Newton, Aparna Parikh, Marjorie L. McCullough, Alpa V. Patel. Weight history and colorectal cancer risk in the Cancer Prevention Study-3 cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2197.

Abstract 4429: Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank cohort

Abstract Background: Dysregulation of metabolic processes contributes to colorectal cancer (CRC) etiology. We aimed to comprehensively evaluate the prospective associations between pre-diagnostic metabolic biomarkers and CRC risk in 230,420 UK Biobank participants. Methods: A total of 249 metabolic biomarkers were measured by nuclear magnetic resonance spectroscopy from baseline plasma samples. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. Subgroup analyses were performed by sex and CRC subsites (i.e., proximal colon, distal colon, rectum). We also conducted factor analyses to identify latent factors and examined their associations with CRC risk. Results: During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified after excluding participants diagnosed with CRC within two years after blood collection. After correcting for multiple testing, 50 metabolic biomarkers, including lipids and lipoproteins, fatty acids, ketone bodies, and inflammation, were significantly associated with incident CRC risk. No statistically significant differences were observed for the biomarker-CRC associations by sex and CRC subsite. In the sensitivity analysis, excluding cholesterol-lowering medication users did not alter the main findings. In factor analyses, we identified a significant association of CRC risk (HR = 1.08; 95% CI = 1.04-1.13; P-value = 6.89×10-5) with a metabolite pattern which was positively correlated with triglycerides and inversely correlated with relative concentrations of omega-6 fatty acids and polyunsaturated fatty acids. Conclusion: We identified multiple metabolic biomarkers and a metabolite pattern associated with CRC risk in a large prospective cohort. These findings suggest lipid metabolism may contribute to carcinogenesis of the colorectum. Citation Format: Fangcheng Yuan, Guochong Jia, Wanqing Wen, Wei Zheng. Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4429.

Abstract 3419: Demographic, health history, and lifestyle factors in association with biomarkers of colorectal cancer prognosis: A pilot study

Abstract Background/Objectives: Multiple demographic, health history, and lifestyle factors have been associated with prognosis of colorectal cancer (CRC), but the mechanisms underlying these associations remain poorly understood. Knowledge of these mechanisms could reveal new strategies to improve outcomes among CRC patients. The primary objective of this project was to explore the association of these factors, which were assessed pre-diagnostically, with expression of two biomarkers in CRC tumors, SPARC and PD-L1, for which lower and higher levels of expression, respectively, have been previously associated with poorer CRC prognosis. Methods: Participants were drawn from the British Columbia Generations Project (BCGP). At the time of recruitment, they completed a detailed questionnaire that ascertained demographic factors (e.g., biological sex and household income), health history (e.g., personal history of CRC screening), and lifestyle factors (daily fruit and vegetable consumption and alcohol consumption). Formalin-fixed paraffin-embedded blocks (FFPE) with adequate volumes of tumor were obtained for 49 incident CRC cases diagnosed within the BCGP. Cores were extracted from the blocks to create tumor tissue microarrays (TMAs). Slides created from thin sections of the TMAs were stained with SPARC and PD-L1 antibodies and then imaged and analyzed to calculate H-scores as measures of expression in both epithelial and non-epithelial tissues. Linear regression analyses were conducted to evaluate associations between the various factors and ln-transformed H-scores. Results: Compared to non-smokers, smokers, on average, had 47% lower SPARC H-scores (p=0.05) in the epithelial tissues of their CRC tumors. Individuals with incomes higher than $74,999/year had 33% higher SPARC H-scores (p=0.04) in their CRC tumor non-epithelial tissues than those who earned less than $74 999/year. Females had 2.8-fold greater PD-L1 H-scores (p=0.005) in their CRC tumor epithelial tissues than males. Compared to those without a history of CRC screening, those with a history of CRC screening had 2.2 and 2.0-fold greater PD-L1 H-scores in their epithelial and non-epithelial CRC tumor tissues, respectively. Conclusion: Larger-scale studies with prognostic data are needed to confirm our findings, but our results suggest that differences in the expression of SPARC and PDL-1 may contribute to the previously observed impacts of some demographic, healthy history, and lifestyle factors on CRC prognosis. Citation Format: Umaimah Zanif, Isabella Tai, Stephen Yip, Sindy Babinszky, Katy Milne, Peter Watson, Rachel Murphy, Parveen Bhatti. Demographic, health history, and lifestyle factors in association with biomarkers of colorectal cancer prognosis: A pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3419.

Metformin’s role in lowering colorectal cancer risk among individuals with diabetes from the Southern Community Cohort Study

BackgroundMetformin, 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. MethodsParticipants 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. ResultsA 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/m2, 0.59 [0.43–0.82] but not among non-obese participants (0.99 [0.65–1.51], p-interaction =.05) ConclusionOur 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.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Metabolomic signatures of inflammation and metabolic dysregulation in relation to colorectal cancer risk.

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. 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. 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. 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.

Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC)

BackgroundAltered lipid metabolism is a hallmark of cancer development. However, the role of specific lipid metabolites in colorectal cancer development is uncertain. MethodsIn a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined associations between pre-diagnostic circulating concentrations of 97 lipid metabolites (acylcarnitines, glycerophospholipids and sphingolipids) and colorectal cancer risk. Circulating lipids were measured using targeted mass spectrometry in 1,591 incident colorectal cancer cases (55% women) and 1,591 matched controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between concentrations of individual lipid metabolites and metabolite patterns with colorectal cancer risk. FindingsOf the 97 assayed lipids, 24 were inversely associated (nominally p<0.05) with colorectal cancer risk. Hydroxysphingomyelin (SM (OH)) C22:2 (ORper doubling 0.60, 95%CI 0.47-0.77) and acylakyl-phosphatidylcholine (PC ae) C34:3 (ORper doubling 0.71, 95%CI 0.59-0.87) remained associated after multiple comparisons correction. These associations were unaltered after excluding cases diagnosed <5 years after blood collection and were consistent according to sex, age at diagnosis, BMI, and colorectal subsite. Two lipid patterns, one including 26 phosphatidylcholines and all sphingolipids, and another 30 phosphatidylcholines, were weakly inversely associated with colorectal cancer. InterpretationElevated pre-diagnostic circulating levels of SM (OH) C22:2 and PC ae C34:3 and lipid patterns including phosphatidylcholines and sphingolipids were associated with lower colorectal cancer risk. This study may provide insight into potential links between specific lipids and colorectal cancer development. Additional prospective studies are needed to validate the observed associations. FundingWorld Cancer Research Fund (reference:2013/1002); European Commission (FP7: BBMRI-LPC; reference:313010).

Association of platinum-based chemotherapy with live birth and infertility in female survivors of adolescent and young adult cancer

ObjectiveLack of treatment-specific fertility risks for female survivors of adolescent and young adult cancer limits counseling on fertility preservation decisions. The objective was to estimate the effect of platinum-based chemotherapy on live birth and infertility after cancer. DesignRetrospective cohort study using U.S. administrative data ParticipantsWe identified incident breast, colorectal and ovarian cancer cases in females ages 15-39 who received platinum-based chemotherapy or no chemotherapy and matched them to females without cancer. ExposurePlatinum-based chemotherapy OutcomesWe estimated the effect of chemotherapy on incidence of live birth and infertility after cancer, overall and after accounting for competing events (recurrence, death, sterilizing surgeries). ResultsThere were 1,287 survivors in the chemotherapy group, 3,192 survivors in the no chemotherapy group, and 34,147 women without cancer, mean age 33. Accounting for competing events, overall five-year live birth incidence was lower in the chemotherapy group (3.9%) versus the no chemotherapy (6.4%) group. Adjusted relative risks versus no chemotherapy and no cancer were 0.61 (95%CI 0.42-0.82) and 0.70 (95%CI 0.51-0.93), respectively. Overall five-year infertility incidence was similar in the chemotherapy group (21.8%) compared to no chemotherapy group (20.7%). The adjusted relative risks versus no chemotherapy and no cancer were 1.05 (95%CI 0.97-1.15) and 1.42 (95%CI 1.31-1.53), respectively. Conclusions and relevanceCancer survivors treated with platinum-based chemotherapy experienced modestly increased adverse fertility outcomes. Estimated effects of platinum-based chemotherapy were affected by competing events, suggesting the importance of this analytic approach for interpretations that ultimately inform clinical fertility preservation decisions.

Associations of serum trimethylamine N-oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort.

Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N-oxide (TMAO) and its precursors, choline, L-carnitine, and betaine. Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L-carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori-selected dietary exposures with the four metabolites were also investigated. TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10[95% CI] =1.90 [CI, 1.24-2.92; p=.003] and 1.26 [1.17-1.36; p<.0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI]=0.77 [0.76-0.79; p<.001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho=0.10; p=.0003). Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.