Risk Of Colorectal Cancer Research Articles

Nitrosyl-heme and heme iron intake from processed meats and risk of colorectal cancer in the EPIC-Spain cohort.

The International Agency for Research on Cancer classified processed meats (PMs) as "carcinogenic" and red meat as "probably carcinogenic" for humans. The possible relationship between colorectal cancer (CRC) risk and the mechanisms involved in the carcinogenesis of PMs have not been established yet. Nitrosyl-heme and heme iron have been proposed as potential-related compounds. The aim of this study was to determine the association between nitrosyl-heme and heme iron intake and CRC risk among participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain study. This prospective study included 38,262 men and women from the EPIC-Spain study. Food consumption was assessed using diet history and composition tables, with heme iron and nitrosyl-heme intake calculated from estimated PM item intakes and laboratory analyses. HR estimates were obtained by proportional hazard models, stratified by age at recruitment and study centre and adjusted for sex, total energy intake, education, smoking, body mass index, waist size, physical activity, lifetime alcohol, fibre, calcium and familiar CRC history. During a mean follow-up of 16.7years, 577 participants were diagnosed with CRC. We found no overall association between nitrosyl-heme (HRT3vsT1: 0.98 (95%IC: 0.79-1.21)) or heme iron intakes (HRT3vsT1: 0.88 (95%IC: 0.70-1.10)) with CRC risk, nor according to tumour subtypes. Our study found no evidence supporting a link between nitrosyl-heme or heme iron intake and CRC risk in Spanish subjects. As research on nitrosyl-heme is preliminary, more heterogeneous studies are necessary to provide more convincing evidence on their role in CRC carcinogenesis.

New role of fat-free mass in cancer risk linked with genetic predisposition

Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E–17 and 1.78E–11) and WBFFM (p = 2.88E–08 and 8.24E–12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass.

Associations of PD-1 and PD-L1 gene polymorphisms with cancer risk: a meta-analysis based on 50 studies.

Programmed death-1 and its ligand-1 (PD-1/PD-L1), immune checkpoints proteins, play a crucial role in anti-tumor responses. A large number of studies have evaluated the relationships of PD-1/PD-L1 polymorphisms with risk of cancer, but evidence for the associations remains inconsistent. Therefore, we performed a meta-analysis to examine the associations between PD-1/PD-L1 single nucleotide polymorphisms (SNPs) and cancer predisposition. Results showed that PD-1.3 and PD-L1 rs17718883 were significantly correlated with overall cancer risk. PD-1.5 was prominently linked with cervical cancer (CC), non-small cell lung cancer (NSCLC), TC (thyroid cancer), brain tumor, AML (acute myelocytic leukemia) and UCC (urothelial cell carcinoma) risk, PD-1.9 with breast cancer (BC), AML, esophageal cancer (EC) and ovarian cancer (OC) risk, and PD-1.3 with colorectal cancer (CRC) and BCC (basal cell carcinoma) risk. PD-1.1 polymorphism slightly elevated BC and OC susceptibility, whereas the rs4143815 variant notably decreased the risk of gastric cancer (GC), hepatocellular carcinoma (HCC) and OC, but increased the risk of BC. PD-1.6 was closely linked with AML risk, PD-L1 rs2890658 with NSCLC, HCC and BC risk, rs17718883 with HCC and GC risk, rs10815225 with GC risk, and rs2297136 with NSCLC and HCC risk. Interestingly, the rs7421861, rs10815225, and rs10815225 markedly reduced cancer susceptibility among Asians. The rs7421861 polymrophism decreased cancer risk among Caucasians, rather than the rs10815225 elevated cancer risk. Our results supported that PD-1 and PD-L1 SNPs were dramatically correlated with cancer risk.

Risk Factors of Early Age Colorectal Cancer among Patients Attending at National Institute of Cancer Research & Hospital

Background: Colorectal cancer (CRC) poses a significant public health burden worldwide, with a notable trend of increasing incidence among individuals aged 20 to 50 years. Understanding the risk factors associated with early-onset CRC is crucial for developing targeted prevention and intervention strategies, particularly in limited-resource settings. Objective: This study aimed to identify and analyze the risk factors contributing to the development of early-onset CRC in a population from a limited-resource country. Method: A comparative study was conducted among 178 CRC patients admitted to the National Institute of Cancer Research & Hospital (NICRH), Dhaka. Patients were divided into two groups: Group-A (age 20-50 years) and Group-B (age >50 years). Demographic and clinical data were collected, and statistical analyses were performed to determine associations between various risk factors and early-onset CRC. Results: The mean age of Group-A subjects was 43.6±7.1 years, significantly younger than Group-B subjects (59.2±9.3 years). Male patients constituted 69.1% of the cohort, with a statistically significant male-to-female ratio of 2.2:1. Higher BMI (≥25) was strongly associated with early-onset CRC (p<0.01). Occupations such as business and middle socioeconomic status were significantly linked to early-onset CRC. Regular exercise (>30 minutes daily) demonstrated a protective effect against CRC development. Consumption of red meat and fast food was associated with a higher risk of CRC, while regular consumption of vegetables was protective. Familial adenomatous polyposis (FAP) presence was significantly associated with early-onset CRC. Conclusions: Male sex, high BMI, specific occupations, dietary factors, and presence of FAP emerged as key risk factors for early-onset CRC. Encouraging regular exercise and promoting healthy dietary habits, particularly reducing red meat and fast-food intake, are crucial in mitigating the risk of early-onset CRC in similar populations.

The causal relationship between cathepsins and digestive system tumors: a Mendelian randomization study.

Multiple studies have confirmed the significant role of cathepsins in the development and progression of digestive system tumors. However, further investigation is needed to determine the causal relationships. We conducted a two-sample bidirectional Mendelian randomization (MR) study using pooled data from a genome-wide association study (GWAS) to assess the causal associations between nine cathepsins (cathepsin B, E, F, G, H, L2, O, S, and Z) and six types of digestive system tumors, including hepatocellular carcinoma (HCC), pancreatic cancer (PCa), biliary tract cancer (BTC), colorectal cancer (CRC), gastric carcinoma (GC), and esophageal cancer (EC). We employed the following methods including inverse variance weighting (IVW), MR-Egger, weighted median (WM), Cochran's Q, MR-PRESSO, MR-Egger intercept test and leave-one-out sensitivity analysis. The STROBE-MR checklist for the reporting of MR studies was used in this study. The risk of HCC increased with high levels of cathepsin G (IVW: p = 0.029, odds ratio (OR) = 1.369, 95% confidence interval (CI) = 1.033-1.814). Similarly, BTC was associated with elevated cathepsin B levels (IVW: p = 0.025, OR = 1.693, 95% CI = 1.070-2.681). Conversely, a reduction in PCa risk was associated with increased cathepsin H levels (IVW: p = 0.027, OR = 0.896, 95% CI = 0.812-0.988). Lastly, high levels of cathepsin L2 were found to lower the risk of CRC (IVW: p = 0.034, OR = 0.814, 95% CI = 0.674-0.985). Our findings confirm the causal relationship between cathepsins and digestive system tumors, which can offer valuable insights for the diagnosis and treatment of digestive system tumors.

Should I Take Aspirin? (SITA): RCT of a decision aid for cancer chemoprevention.

Background Australian guidelines recommend that all people aged 50-70 years old consider taking low-dose aspirin to reduce the risk of colorectal cancer (CRC). Aim To determine the effect of a consultation with a researcher in general practice using a decision aid about taking low-dose aspirin to prevent CRC on informed decision-making and low-dose aspirin uptake compared to a general CRC prevention brochure. Design and Setting Individually randomised controlled trial in six general practices in Victoria, Australia, from October 2020 to March 2021. Method Patients aged 50-70 years attending a general practitioner (GP) were recruited consecutively. The intervention was a consultation using a decision aid to discuss taking aspirin to reduce CRC risk; control consultations discussed reducing CRC risk generally. The self-reported co-primary outcomes were informed choices about taking aspirin at one month and low-dose aspirin uptake at six months. Results 261 participants (86% of eligible patients) were randomised into trial arms (129 intervention, 132 control). 17.7% (20/113) of intervention and 7.6% (9/118) control participants reported making an informed choice at one month, an estimated 9.1% (95% CI 0.29% to 18.5) between-arm difference in proportions [odds ratio (OR) 2.47 (97.5% CI:0.94 to 6.52) p=0.074]. The proportions of individuals who reported using aspirin at six months were: 10.2% (12/118) intervention vs 13.8% (16/116) control (estimated between-arm difference: -4.0% (95% CI: -13.5 to 5.5); [OR= 0.68 (97.5% CI:0.27 to 1.70), p= 0.692]. Conclusion The decision aid improved informed decision-making; but has little effect on long-term regular use of aspirin to reduce CRC risk.

Abstract 755: Fecal microbial dysbiosis is associated with colorectal cancer risk

Abstract Although there is evidence of an association between the fecal microbiota and colorectal cancer (CRC) risk in epidemiologic studies, there is a lack of data from large-scale population-based studies. To address this gap, we assessed the dysbiosis of the fecal microbiome in a large-scale study in Korea. We recruited 287 CRC patients from the Center for Colorectal Cancer, National Cancer Center Hospital, Korea to perform 16S rRNA gene sequencing of fecal samples. A total of 287 age- and sex-matched healthy participants were selected from 890 cohort of healthy Koreans that are publicly available (PRJEB33905). The microbial dysbiosis index (MDI) was calculated based on the differentially abundant species. The association between MDI and CRC risk was observed using conditional logistic regression. Alpha-diversity indices were not significantly different between CRC cases and controls. The first three principal coordinates derived by a principal coordinate analysis (PCoA) based on weighted UniFrac distance explained 41.24% of the overall microbial diversity, with a significant divergence of the microbial composition between CRC patients and controls (PERMANOVA p=0.001). Three enterotypes were found based on CRC patients’ microbial composition. Those who were in the third tertile of the MDI showed a significantly increased risk of CRC in the total population (OR: 6.59, 95% CI: 3.83-11.33, p-trend<0.001) compared to those in the lowest tertile. Similar results were found for men (OR: 6.58, 95% CI: 3.17-13.63, p-trend<0.001) and women (OR: 6.69, 95% CI: 2.91-15.37, p-trend<0.001). Dysbiosis in the fecal microbiota may be associated with an increased risk of CRC. Due to the potentially modifiable nature of the gut microbiota, our findings may have implications for CRC prevention among Koreans. Key words: Fecal microbiome, 16S rRNA gene sequencing, Microbial dysbiosis, Colorectal cancer Citation Format: Jeongseon Kim, Madhawa Gunathilake, Hyun Yang Yeo, Jae Hwan Oh, Byung Chang Kim, Nayoung Han, Bun Kim, Hyojin Pyun, Mi Young Lim, Young-Do Nam, Hee Jin Chang. Fecal microbial dysbiosis is associated with colorectal cancer risk [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 755.

Age-related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high-risk cases.

As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the β-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning-based digital image analysis with fluorescence-immunohistochemistry, we assessed SQLE, GSK3βpS9 (GSK3β activity inhibition through serine 9 phosphorylation at GSK3β), p53 wild-type (p53WT), and p53 mutant (p53MT) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53WT, and p53MT and increase in GSK3βpS9 levels, all associated with the substantial accumulation of intra-tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression-free survival in grade 2-3 CRC patients aged over 50. SQLE and GSK3βpS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53WT, p53MT, and GSK3βpS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging-linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3βpS9, for older patients at elevated risk of CRC.

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 6142: Interactions of processed meat and red meat intake with pathway-based polygenic risk scores for colorectal cancer: A novel approach for PRSs construction

Abstract Introduction: Colorectal cancer (CRC) is the third most common cancer, and second cause of cancer death worldwide. Established CRC risk factors (E) include high red meat and processed meat intake. Genome-wide association studies (GWAS) have reported over 200 genetic variants associated with CRC risk. We used functional annotation data to identify subsets of GWAS variants within known pathways and constructed corresponding pathway Polygenic Risk Scores (pPRS). We evaluated pPRS by E interactions to determine whether genes within specific pathways interacted with meat intake to impact CRC risk. Methods: A pooled sample of 54,531 CRC controls and 48,260 cases of European ancestry from 27 studies were analyzed. Study-specific quartiles for red and processed meat intake were generated through in-person interviews and structured self-administered questionnaires. Variants were imported to AnnoQ for annotation (n=203) and analyzed for overrepresentation in PANTHER-reported pathways with Fisher’s exact test. Standard approaches were used to compute polygenic risk score weights relating the 203 variants to CRC. The subset of weights corresponding to each of five pathways were then used to compute the corresponding pPRS. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red meat and processed meat intake. Results: A total of 34 unique variants were overrepresented in five pathways: Apoptosis signaling, Alzheimer disease-presenilin, Wnt-signaling, Gonadotropin-releasing hormone receptor, and TGF-beta signaling. We found a statistically significant interaction between TGF-beta-pPRS and red meat intake (p = 0.0012). Stratified analyses reported a dose-response trend in the red meat and CRC risk association, with decreasing estimates of red meat and CRC risk association, comparing first to fourth quartiles of meat intake, with increasing quartiles of TGF-beta-pPRS: 13% (Q1), 12% (Q2), 7% (Q3), and 6% (Q4). This association remained significant after adjustment for all other variants (p = 0.0013), and all other pPRS with variants that did not overlap with the TGF-beta-pPRS (p = 0.0012). Independent GxE interaction models for individual variants that were included in the TGF-beta pathway showed significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.013 & 0.0108, respectively). We did not find significant pPRS x red meat interactions for the other four pathways or with any pPRS x processed meat. Conclusion: This pathway-based interaction analysis revealed a statistical interaction between SNPs in the TGF-beta pathway and red meat consumption that impacts CRC risk. These findings shed light into the possible mechanistic link between CRC risk and red meat consumption. Citation Format: Joel Sanchez Mendez, Mariana C. Stern, Yubo Fu, John Morrison, Juan P. Lewinger, Eric Kawaguchi, Bryan Queme, Huaiyu Mi, Flora Qu, Ulrike Peters, Li Hsu, Stephen B. Gruber, Li Li, Michelle Cotterchio, Loic Le Marchand, Andrew J. Pellat, Elizabeth A. Platz, W James Gauderman. Interactions of processed meat and red meat intake with pathway-based polygenic risk scores for colorectal cancer: A novel approach for PRSs construction [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 6142.

Abstract 3431: Genetically determined circulating lactase/phlorizin hydrolase concentrations and risk of colorectal cancer: A two-sample mendelian randomization study

Abstract Background: Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Despite its established connection with genetic, dietary, and lifestyle factors, gaps remain in the understanding of its etiology. Lactase-phlorizin hydrolase (LPH) plays a critical role in milk digestion and influences crucial nutrient absorption and gut microbiota composition. A direct relationship of CRC risk with LPH level remains unexplored. Our study aims to elucidate the potential causal link between genetically determined LPH levels and CRC risk. Methods: We applied a two-sample Mendelian Randomization (MR) strategy to investigate the causal link between elevated LPH levels and CRC risks. Genetic instruments for LPH (one cis-variant and three trans-variants) 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, specifically colon and rectal cancer. Results: Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH level and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of genetically predicted elevated LPH levels with reduced risks for both colon cancer (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 different datasets. Conclusions: Our study suggests an inverse relationship between genetically determined LPH level and CRC risk. Further exploration is warranted to unveil the underlying mechanisms and validate LPH’s potential role in CRC prevention. Citation Format: Sihao Han, Jiemin Yao, Hajime Yamazaki, Samantha Streicher, Jianyu Rao, Roch Nianogo, Zuo-Feng Zhang, Brian Huang. Genetically determined circulating lactase/phlorizin hydrolase concentrations and risk of colorectal cancer: A two-sample mendelian randomization 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 3431.

Abstract 3428: Association of adipokines and inflammation biomarkers with cancer risk in men

Abstract Using pre-diagnosis fasting plasma samples from 4,040 participants of the Shanghai Men’s Health Study which enrolled 61,464 men ages 40-70 during 2001-2006, we prospectively evaluated the associations of adipokines and inflammation biomarkers with cancer risk. Levels of leptin, resistin, adiponectin, plasminogen activator inhibitor type-1 (PAI-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNFa), monocyte chemoattractant protein-1 (MCP-1), and insulin were measured by Luminex assays, and C-reactive protein (CRP), measured by ACE Clinical Chemistry System. Biomarker levels were categorized by tertile distribution. The Cox regression model was applied to derive hazard ratios (HR) and 95% confidence intervals (CI) for cancer risk in association with biomarkers with adjustment for potential confounders. Principle component analysis (PCA) was performed to assess associations with multiple biomarkers, and tertile scores for each component were used in analyses. During 15-years of follow-up, 318 cancer cases were identified, including 85 lung, 49 gastric, 17 liver, and 61 colorectal cancer (CRC) cases. Analyses adjusted for age, education and income showed that 3rd vs 1st tertile of TNFa (HR=1.7, 95%CI=1.0-3.0) and adiponectin (HR=4.0, 95%CI=1.1-14.4) was associated with lung and liver cancer risk, respectively. High levels of leptin, insulin, and CRP were each associated with CRC risk: respective HRs were 2.3 (95%CI=1.1-4.7), 2.1 (95%CI=1.0-4.2), and 2.0 (95%CI=1.1-3.9). After further adjustment for known cancer risk factors, TNFa-lung cancer (HR=1.8, 95%CI=1.1-3.1); leptin-CRC (HR= 3.2, 95%CI=1.3-7.7); insulin-CRC (HR=2.1, 95%CI=1.0-4.5); and CRP-CRC (HR=2.0, 95%CI=1.0-4.0) associations remained statistically significant. The adiponectin-lung cancer association lost significance. PCA identified 4 principal components (PC). High PC1 score (main loadings: TNFa, leptin, and insulin) was associated with CRC risk (HR=2.3, 95%CI=1.1-5.0 for 3rd vs 1st tertile ptrend=0.02). High PC2 score (main loadings: adiponectin, IL-8, MCP-1) and PC3 (main loadings: resistin and PAI-1) were associated with liver cancer risk: HR=5.2 (95%CI=1.1-24.3) for the 3rd vs 1st tertile, ptrend=0.03 and HR=4.7 (95%CI=1.0-21.7), for the 3rd vs 1st tertile, ptrend=0.03, respectively. High PC4 score (main loadings: IL-6 and CRP) was associated with lung cancer risk (HR=1.7, 95%CI=1.0-3.0, for the 3rd vs 1st tertile, ptrend=0.04). These associations, except the PC1-CRC association, lost significance after further adjustment of known cancer risk factors. Our study found that high plasma levels of insulin, CRP, and their combination were associated with CRC risk, high resistin and adiponectin levels with liver cancer risk, and high TNFa levels with lung cancer risk. Some biomarker-cancer associations may be explained by their correlations with known cancer risk factors, especially smoking. Citation Format: Douglas DeMoulin, Hui Cai, Qiuyin Cai, Wei Zheng, Xiao-Ou Shu. Association of adipokines and inflammation biomarkers with cancer risk in men [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 3428.

Abstract 6151: Relationship between polygenic risk score, lifestyle factors, and colorectal cancer risk

Abstract Although heritable factors are estimated to explain up to 35% of colorectal cancers (CRC), most are diagnosed in people without a family history of CRC suggesting that inherited genetic variants, environmental factors, or a combination of both, contribute to CRC risk. We explored the relationship between a polygenic risk score (PRS) for CRC risk and lifestyle risk factors to understand whether individuals with higher genetic risk, who do not develop CRC, engage in healthier lifestyle behaviors, or conversely, whether those with lower genetic risk, who do develop CRC, engage in riskier behaviors in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Using summary statistics obtained from a large independent GWAS meta-analysis of CRC by the GECCO consortium, we developed a genome-wide PRS for CRC using SBayesR and applied it to participants of European ancestry genotyped in the PLCO Trial (n=74,396). For all subjects, we computed an environmental (E) score based on 19 lifestyle risk factors for CRC, a WCRF/AICR score that measured adherence to the 2018 Cancer Prevention recommendations, and a 2015 healthy eating index (HEI) with higher values indicating healthier lifestyle profiles. We used t-tests to evaluate differences in lifestyle scores between CRC-free participants in the highest quartile of PRS and incident CRC cases in the lowest quartile of PRS. To examine the correlations between the PRS and lifestyle scores, we performed multivariable linear regression models regressing PRS on each lifestyle score. We used multivariable Cox hazards regression models to compute hazard ratios and 95% confidence intervals for CRC risk; multiplicative interactions between PRS and lifestyle scores were evaluated using the Wald test for the interaction terms. During the 15 years follow-up period, a total of 1,052 CRC cases were diagnosed. Individuals in the highest quartile of PRS who remained cancer-free were more likely to engage in healthier behaviors than those in the lowest quartile of PRS who were diagnosed with incident CRC (E-score: -0.01 vs. -0.18, WCRF/AICR score: -0.05 vs. -0.32, HEI score: 0.06 vs. -0.13); however, differences were not statistically significant (P value: 0.1 to 0.4). PRS and lifestyle scores were significantly (all P <0.0001), albeit weakly (β: -0.02 to -0.03), associated among participants who remained CRC-free but not among CRC cases (P: 0.1 to 0.3). PRS-lifestyle score interactions were not statistically significant (P: 0.2 to 0.4). Although the differences and multiplicative interaction models were not statistically significant, we found that individuals with a higher PRS who remained CRC-free were slightly more likely to engage in healthier behaviors than those at a lower genetic score who developed CRC. Additional studies with larger sample size are warranted to further explore the interplay between genetic risk and lifestyle factors related to CRC risk. Citation Format: Wen-Yi Huang, Erikka Loftfield, Rebecca Landy, Difei Wang, Hormuzd A. Katki, Jianxin Shi, Lingxiao Wang, Mitchell J. Machiela, Neal D. Freedman, Sonja I. Berndt. Relationship between polygenic risk score, lifestyle factors, and colorectal cancer risk [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 6151.

Abstract 120: A closer Look at colorectal cancer risk: Insights from the complex relationship of HIV, helminths, and immune responses

Abstract The advent of antiretroviral therapy has markedly increased the survival rates of individuals with human immunodeficiency virus (HIV). However, this demographic, particularly in low-middle-income countries (LMICs) where HIV-helminth co-infections are prevalent, remains susceptible to infections. The intricate interplay between helminth infections and HIV susceptibility, often inducing immunological phenotypes that heighten vulnerability, remains poorly understood. Studies have shown the association between HIV-helminth co-infections and elevated susceptibility to colorectal cancer (CRC), introducing an additional layer of health concerns for this already vulnerable population. This retrospective observational study delves into the profound effects of HIV-helminth co-infections on immune responses, with a specific focus on type 2 T helper (Th2) cell immunomodulation and susceptibility to CRC. Utilizing samples from a master project (n=414), 80 systematically randomized individuals were categorized into uninfected control, HIV-infected only, helminth-infected only, and HIV-helminth co-infected groups. Parasite detection employed the Kato-Katz technique, and serum testing was conducted for helminth-specific antibodies. Serological HIV testing, viral load categorization, white blood cell counts, and differential analyses were performed. Human ProcartaPlex Panel 1 was used for cytokine profiling of immune stimulatory and inhibitory soluble proteins. A significant reduction in B and T lymphocyte attenuator (BTLA) (p=0.049) in helminth infections compared to the control. The association of BTLA with its ligand, herpesvirus entry mediator (HVEM), establishes a direct link between the CD28 and tumor necrosis factor receptor (TNFR) families, triggering wide-ranging and robust immune responses. Subsequently, a notable reduction in CD28 was observed in HIV-infected subjects (p=0.003), followed by helminth-infected and HIV-helminth co-infected individuals (p=0.03) compared to the control. Furthermore, programmed death ligand-2 (PD-L2) expression, a major contributor to alternatively activated macrophage polarization during helminth infections, was significantly increased in the HIV-helminth co-infected group (p = 0.05), favoring a shift towards Th2 immune responses. These observed alterations underscore the complexity of the immunological interplay in co-infected individuals, emphasizing an additional risk factor for colorectal cancer development. This necessitates a comprehensive understanding, providing valuable insights for the development of therapeutic strategies in LMICs and similar settings, addressing the heightened risk of CRC within this population. Citation Format: Botle P. Damane, Thanyani V. Mulaudzi, Sayed S. Kader, Ropo E. Ogunsakin, Pragalathan Naidoo, Zodwa Dlamini, Zilungile L. Mkhize-Kwitshana. A closer Look at colorectal cancer risk: Insights from the complex relationship of HIV, helminths, and immune responses [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 120.

Abstract 2317: Development and validation of a colorectal cancer prediction model: A nationwide cohort-based study

Abstract Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is a major cause of cancer-related mortality. Early diagnosis is critical to increase survival rates. While CRC screening has shown significant benefit, adherence remains low, and there is a need for better tools to identify high-risk patients. Risk prediction models were demonstrated to identify such patients. Aim: To establish an individualized risk prediction model for CRC diagnosis based on Electronic Health Records (EHR). Methods: This is a retrospective cohort study utilizing EHR data of Clalit Health Services (CHS) members aged 50-74 that were eligible for CRC screening, from January 2013 to January 2019. The model was trained to predict CRC diagnosis within two years using approximately 20,000 EHR features including socio-demographic information, laboratory results and medical history. Model performance, as a complementary screening method, was evaluated. Results: The study included 2679 subjects with CRC diagnosis and 1,133,713 subjects without CRC diagnosis. The model was trained on subjects from 2013-2017, and performance was validated on subjects from 2019 and a cohort of subjects that underwent fecal occult blood test (FOBT). Incidence values of CRC among subjects in the top 1% risk scores were higher than baseline (2.3% vs. 0.3%; lift 8.38; P-value <0.001). Characteristics of subjects by risk scores percentiles are presented in Table 1. Cumulative event probabilities increased with higher model scores, indicating a correlation between predicted and actual risk of CRC diagnosis. Model-based risk stratification among subjects with a positive FOBT, identified subjects with more than twice the risk for CRC compared to FOBT alone. Conclusions: We developed an individualized risk prediction model for CRC that can be utilized as a complementary decision support tool for healthcare providers to precisely identify patients at high risk for CRC and refer them to confirmatory testing. Citation Format: Samah Hayek. Development and validation of a colorectal cancer prediction model: A nationwide cohort-based 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 2317.

Abstract 2156: Exploring barriers to colorectal cancer screening among adult male immigrants in Salt Lake City

Abstract Background: The United States (U.S) foreign-born population aged 65+ increased substantially between 1990 and 2010 with migrants from Africa and the Middle East being a part of these new refugee admissions. According to 2010 data, socioeconomic disparities and reduced access to health care is common in this population with 16 percent of foreign-born elderly living below the poverty threshold in comparison with 8 percent of U.S.-born elderly. Colorectal Cancer (CRC) is the second leading cause of cancer related deaths in the U.S despite being easily preventable and treatable. Studies among male African Americans reveal a CRC incidence >20% higher than what obtains among whites. Since, genetic factors are believed to contribute as much as 35% to the overall risk of CRC, male adult immigrants aged 45 years and above from Africa and the Middle East may be at increased risk of developing the disease. Determining CRC screening uptake in this population will be critical in planning interventions which may ultimately reduce disparities in CRC-related morbidity and mortality in the future. Methods: We conducted a mixed methods study comprising administration of questionnaires and organizing four Focus Group Discussion (FGD) sessions among adult males in Salt Lake City who identified as refugees from Africa or the Middle East. The sessions were audio-taped, transcribed and coded using the Dedoose software. Results: We had thirty-one participants who were between 45 and 64 years of age. Twenty-five of them (83%) reported awareness of the existence of CRC screening tests. Ten participants (33%) had undergone a CRC test in the past. However, only nine participants (30%) indicated that they will be willing to participate (WTP) in CRC screening if offered for free. Increased WTP was associated with younger age (OR=1.45, 95% CI: 1.23-1.81), length of stay in the United States (OR=1.41, 95% CI: 1.13-1.78) and higher education (OR= 1.26, 95% CI 1.13-1.37). Three major themes identified in the FGDs include: (1) Mistrust - distrust of the US health system (2) Fear - fear of cancer and nature of test and (3) Fatalism - the belief that screening cannot lead to cancer cure. Conclusion: The low level of WTP in CRC screening tests among the respondents may be associated with past experiences. There may be a need to consider the correlates of increased WTP and explore culture-specific CRC prevention measures in planning interventions designed to improve screening uptake in this population. Citation Format: Olanrewaju Olusola Onigbogi, Kebba Kah, Kolawole Okuyemi. Exploring barriers to colorectal cancer screening among adult male immigrants in Salt Lake City [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 2156.

Abstract 7305: Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium

Abstract Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. CRC usually develops from adenomas (CRC precursors) after a long latency period. Prevention is crucial in reducing CRC incidence and progression to cancer. Among several prevention options, calcium has been a widely considered chemo-preventative agent. Aims: Calcium plays a vital role in the regulation of epithelial cell differentiation, which is essential for epithelial growth control. Epidemiological studies have demonstrated that adequate calcium intake is crucial for protection against colonic polyp formation and colorectal cancer. However, recent interventional trials with calcium have had only modest and mixed results, and the question is how to improve efficacy. One potential strategy is to use calcium in combination with additional minerals and trace elements. Results: Our preclinical studies employing monolayer cultures with CRC cell lines and colon organoids cultures from colon polyps have shown that a calcium-rich mineral combination derived from fossilized red algae (Aquamin) is more effective than calcium alone in inducing differentiation, suppressing growth and upregulation of calcium-sensing receptor. When colonic adenomas in culture were subjected to differential proteomic analysis, Aquamin upregulated several proteins involved in proliferation suppression, DNA mismatch repair and inducing differentiation, and apoptosis. Two long-term mouse studies have demonstrated that Aquamin is more effective in suppressing polyp & CRC incidence compared to calcium alone. Based on these findings, we conducted a 90-day FDA-approved trial (a pilot study with ten subjects per arm) comparing the two interventions in human subjects at risk for CRC. Results showed that Aquamin treatment reduced proliferation and increased cell differentiation observed by immunohistochemistry. Proteomic analysis also revealed that the minerals upregulated several proteins related to growth suppression, inducing differentiation and those contributing to cell-cell and cell-matrix adhesion functions and downregulated proteins involved in proliferation and nucleic acid metabolism. Conclusion: These results provide convincing evidence that a multi-mineral combination derived from red algae can provide benefits in preventing CRC that are not seen with calcium alone. Further studies, such as a polyp-prevention trial in human subjects, are warranted to advance these CRC prevention efforts. Citation Format: Isabelle Harber, Shannon McClintock, James Varani, Muhammad N. Aslam. Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium [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 7305.

Abstract 3434: Effect modification by levels of sex hormones in the association between adiposity and cancer incidence in the UK Biobank

Abstract Introduction: The association between adiposity and cancer risk differs between sexes for some cancer types. Methods: We prospectively examined adiposity in relation to cancer incidence according to sex hormones in the UK Biobank. Adiposity was assessed by body mass index (BMI) and visceral adipose tissue (VAT), the latter predicted using determinants of age, height, weight, hip circumference, waist circumference, and race. Serum sex hormone binding globulin (SHBG), testosterone, and estradiol were measured using a biochemistry assay and were classified as high or low based on median levels. Cancer incidence was ascertained using ICD-10 codes through cancer registry linkage. For cancer types showing a sex difference in the association between adiposity and cancer incidence, we assessed multiplicative and additive interaction with sex hormones in men and women separately and corrected for multiple testing using false discovery rate. We used Cox regression to calculate the multivariable hazard ratio (HR) of cancer per increase between the 90th to 10th percentile of adiposity (BMI or predicted VAT). Results: During a median follow-up of 13.1 years, we documented 23,964 and 21,045 incident cancer cases among 217,460 men and 256,163 women, respectively. Adiposity showed a much stronger association with higher risk of colorectal, esophageal, and liver cancers in men than women. In men, BMI was more strongly associated with higher risk of colorectal cancer in low vs. high levels of SHBG (HR (95%CI) of 1.47 (1.31-1.64) vs. 1.12 (0.94-1.33) (adjusted Pinteraction = 0.027). In contrast, BMI showed a stronger association in high vs. low levels of SHBG with esophageal (HR = 2.39 vs. 1.62) and liver cancers (HR = 3.24 vs 1.96) in men (adjusted Pinteraction = 0.038 and 0.027, respectively). Among women, BMI was associated with a higher risk of esophageal cancer in those with low SHBG (HR=1.68) but not in those with high SHBG (HR=0.64) (adjusted Pinteraction = 0.025). Similar patterns were observed for predicted VAT. Men with high SHBG levels and high adiposity (BMI and predicted VAT) had 7.63 (5.08-11.46) and 8.92 (5.72 to 13.90), respectively, times higher risk of liver cancer compared to men with low SHBG levels and low adiposity. No effect modification by estradiol or testosterone was detected for any of the cancers studied. Conclusions: The association between adiposity and colorectal, esophageal, and liver cancer differed by sex. SHBG may be an important factor underlying these differences. Citation Format: LeeAnn Lucas, Yujia Lu, Edward L. Giovannucci, Mingyang Song. Effect modification by levels of sex hormones in the association between adiposity and cancer incidence in the UK Biobank [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 3434.

Abstract 6885: Investigating a novel role of DCLK1 isoforms in colitis and colitis associated colon cancer

Abstract Chronic intestinal inflammation in patients diagnosed with inflammatory bowel disease (IBD) significantly increases their risk of colorectal cancer (CRC). Despite the rising global frequency of IBD, the precise mechanisms that regulate the transition from IBD to colon cancer are poorly understood. Doublecortin-like kinase 1 (DCLK1) is a protein with two major isoforms, DCLK1-L and DCLK1-S. Previous studies have shown that hypermethylation of the DCLK-1α promoter encoding DCLK1-L, particularly in colorectal cancer, allows switching to the DCLK1-S isoform that confers an invasive tumor phenotype. The DCLK1-L is a tuft cell marker that protects against colitis by sensing and eliminating gut pathogenic infection through various mechanisms. On the contrary, the role of DCLK1-S in colitis and colitis-associated cancer has not been thoroughly investigated. Studies from our lab have identified a marked elevation of DCLK1-S in tissue samples of IBD patients. We also recently discovered that DCLK1-S is predominantly expressed in Ly6G+; MHCII- neutrophils, which coincide with elevated levels of inflammation and tissue damage in the colon. To further understand the role of DCLK1 isoforms in driving the progression of colitis to colon cancer, we bred Dclk1fl/fl mice with MRP8-Cre-ires/GFP mice to generate Dclk1fl/fl;MRP8-Cre+/- that eliminates DCLK1-L upon tamoxifen injection resulting in sustained expression of DCLK1-S in the granulocytes especially neutrophils. When infected with Citrobacter rodentium (CR), MRP8;Dclk1−/− mice compared to MRP8;Dclk1+/− or WT mice developed more severe colitis. We have also discovered a novel interaction between DCLK1-S and MMP13 in an unbiased docking study that correlated with significant co-localization of DCLK1-S with MMP13 in the colons of CR-infected mice. Employing a knock-in mice over-expressing the DCLK1-S +19 under the CAG promoter, the DCLK1-MMP13 co-localization correlated with severe ulceration and colitis with loss of crypts and immune cell infiltration including Ly6G+ neutrophils. Studies are underway to see if the severity of colitis in MRP8;Dclk1−/− mice translates into enhanced tumorigenesis and to see if potential interaction between DCLK1-S and MMP13 could provide a plausible mechanism of colitis progression to colon cancer through ECM remodeling and tissue damage. Citation Format: Kafayat Aderonke Yusuf, Badal C. Roy, Shrikant Anant, Shahid Umar. Investigating a novel role of DCLK1 isoforms in colitis and colitis associated colon cancer [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 6885.