Colorectal Cancer Risk In Men Research Articles

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.

Dietary Inflammatory and Insulinemic Potentials, Plasma Metabolome and Risk of Colorectal Cancer.

The inflammatory and insulinemic potentials of diets have been associated with colorectal cancer risk. However, it is unknown whether the plasma metabolite profiles related to inflammatory diets, or to insulinemic diets, underlie this association. The aim of this study was to evaluate the association between metabolomic profile scores related to the food-based empirical dietary inflammatory patterns (EDIP), the empirical dietary index for hyperinsulinemia (EDIH), and plasma inflammation (CRP, IL-6, TNFα-R2, adiponectin) and insulin (C-peptide) biomarkers, and colorectal cancer risk. Elastic net regression was used to derive three metabolomic profile scores for each dietary pattern among 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study, and associations with CRC risk were examined using multivariable-adjusted logistic regression, in a case-control study of 524 matched pairs nested in both cohorts. Among 186 known metabolites, 27 were significantly associated with both the EDIP and inflammatory biomarkers, and 21 were significantly associated with both the EDIH and C-peptide. In men, odds ratios (ORs) of colorectal cancer, per 1 standard deviation (SD) increment in metabolomic score, were 1.91 (1.31-2.78) for the common EDIP and inflammatory-biomarker metabolome, 1.12 (0.78-1.60) for EDIP-only metabolome, and 1.65 (1.16-2.36) for the inflammatory-biomarkers-only metabolome. However, no association was found for EDIH-only, C-peptide-only, and the common metabolomic signatures in men. Moreover, the metabolomic signatures were not associated with colorectal cancer risk among women. Metabolomic profiles reflecting pro-inflammatory diets and inflammation biomarkers were associated with colorectal cancer risk in men, while no association was found in women. Larger studies are needed to confirm our findings.

Dietary intake of total, heme and non-heme iron and the risk of colorectal cancer in a European prospective cohort study.

Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive. We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method. Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HRQ5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HRQ5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HRQ5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HRQ5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HRQ5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HRQ5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources.

Plant-based dietary patterns defined by a priori indices and colorectal cancer risk by sex and race/ethnicity: the Multiethnic Cohort Study

BackgroundPlant-based diets assessed by a priori indices are associated with health outcomes. This study investigated the associations between pre-defined indices of plant-based diets and risk of colorectal cancer (CRC) and evaluated whether the association varies by sex, race and ethnicity, and anatomic subsite of tumors.MethodsA total of 79,952 men and 93,475 women who participated in the Multiethnic Cohort Study were included. Primary outcome was incidence of invasive CRC. Cox models were used to estimate the risk of CRC across quintiles of three plant-based diet scores: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI).ResultsDuring a mean follow-up of 19.2 years, 4976 incident CRC were identified. Among men, multivariable-adjusted HR (95% CI) for the highest vs. lowest quintiles was 0.77 (0.67–0.88) for PDI, and 0.80 (0.70–0.91) for hPDI, while no significant association was found for uPDI among men and for all indices among women. In men, the inverse association for PDI was stronger in Japanese American, Native Hawaiian, and White groups than African American or Latino group (P for heterogeneity = 0.01) and for left colon and rectal tumors than right tumors (P for heterogeneity = 0.005), whereas the decreased risk with hPDI was found consistently across racial and ethnic groups and subsites.ConclusionsGreater adherence to plant-based diets rich in healthy plant foods and low in less healthy plant foods is associated with a reduced risk of CRC in men, but not in women. The strength of the association among men may vary by race and ethnicity and anatomic subsite of tumors.

Fasting Blood Glucose Variability and Unfavorable Trajectory Patterns Are Associated with the Risk of Colorectal Cancer.

Background/AimsThe relationship between fasting blood glucose (FBG) variability and colorectal cancer (CRC) remains ill-defined. This study aimed to evaluate the association of FBG variability with CRC risk in the healthy population without overt diabetes.MethodsIn the data from the Korean National Health Insurance Service-Health Screening Cohort, we included individuals examined by FBG testing at least 3 times between 2002 and 2007. FBG variability was calculated using standard deviation (SD) and coefficient of variation (CV).ResultsRegarding FBG variability, an increase in the quintile of SD or CV was independently associated with CRC risk (all p for trend <0.01). When the change in FBG was classified into six trajectory patterns, unfavorable trajectory patterns (high stable and upward) were significantly associated with increased CRC risk (hazard ratio [HR] 2.30, p=0.003; HR 1.19, p=0.007, respectively). In subgroup analyses according to the sex, a significant association between FBG variability (SD or CV) and CRC risk was observed in men but not in women. The high stable and upward pattern were also associated with CRC risk in men (HR 2.47, p=0.002; HR 1.21, p=0.012) but not in women.ConclusionsThis study identified that FBG variability and unfavorable trajectory patterns were significantly associated with increased CRC risk in the healthy population without overt diabetes. Our findings suggest that FBG variability as well as FBG itself may be a predictive factor for the development of CRC.

Prevalent diabetes and risk of total, colorectal, prostate and breast cancers in an ageing population: meta-analysis of individual participant data from cohorts of the CHANCES consortium.

We investigated whether associations between prevalent diabetes and cancer risk are pertinent to older adults and whether associations differ across subgroups of age, body weight status or levels of physical activity. We harmonised data from seven prospective cohort studies of older individuals in Europe and the United States participating in the CHANCES consortium. Cox proportional hazard regression was used to estimate the associations of prevalent diabetes with cancer risk (all cancers combined, and for colorectum, prostate and breast). We calculated summary risk estimates across cohorts using pooled analysis and random-effects meta-analysis. A total of 667,916 individuals were included with an overall median (P25-P75) age at recruitment of 62.3 (57-67) years. During a median follow-up time of 10.5 years, 114,404 total cancer cases were ascertained. Diabetes was not associated with the risk of all cancers combined (hazard ratio (HR) = 0.94; 95% confidence interval (CI): 0.86-1.04; I2 = 63.3%). Diabetes was positively associated with colorectal cancer risk in men (HR = 1.17; 95% CI: 1.08-1.26; I2 = 0%) and a similar HR in women (1.13; 95% CI: 0.82-1.56; I2 = 46%), but with a confidence interval including the null. Diabetes was inversely associated with prostate cancer risk (HR = 0.81; 95% CI: 0.77-0.85; I2 = 0%), but not with postmenopausal breast cancer (HR = 0.96; 95% CI: 0.89-1.03; I2 = 0%). In exploratory subgroup analyses, diabetes was inversely associated with prostate cancer risk only in men with overweight or obesity. Prevalent diabetes was positively associated with colorectal cancer risk and inversely associated with prostate cancer risk in older Europeans and Americans.

Soluble Receptor for Advanced Glycation End-products (sRAGE) and Colorectal Cancer Risk: A Case-Control Study Nested within a European Prospective Cohort.

Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation. To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively. Higher sRAGE concentrations were inversely associated with colorectal cancer (ORQ5vs.Q1, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (ORQ5vs.Q1, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (ORQ5vs.Q1, 1.00; 95% CI, 0.68-1.48; P heterogeneity for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of ADAM10) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99). Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within ADAM10 gene, pertaining to RAGE shedding, was associated with colorectal cancer risk. Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.

Metabolic Syndrome and Colorectal Cancer Risk: Results of Propensity Score-Based Analyses in a Community-Based Cohort Study.

Background: This study aimed to determine the effects of metabolic syndrome (MetS) on colorectal cancer (CRC) using propensity score (PS) methods. Methods: The study subjects were 2417 men and 4568 women from the Korean National Cancer Center (KNCC) Community Cohort enrolled between 2003 and 2010. Odds risks (ORs) and 95% confidence intervals (CIs) using PS matching analysis, regression models adjusted by the PS or stratified into five strata according to PS, and PS weighting methods were calculated. Results: In women, MetS and abnormally high triglyceride (TG) levels were associated with CRC risk using the PS matching analysis (ORs, for MetS, 2.19 (95% CI, 1.10–4.33); for abnormal TG levels, 2.08 (95% CI, 1.07–4.02)). However, there were no significant associations between MetS and TG levels and CRC risk in men. Conclusions: Our study might provide additional evidence that deteriorated metabolic profiles increase the risk of CRC in women rather than men. Thus, this may have an important role in effective population-level interventions for deteriorated metabolic profiles at an early stage.

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

BackgroundBilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.MethodsIn a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10−8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.ResultsThe associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04–1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76–0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02–1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96–1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).ConclusionsAdditional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

Dietary fatty acids and colorectal cancer risk in men: A report from the Shanghai Men's Health Study and a meta-analysis.

Evidence from animal models suggests that dietary fatty acids have both anticancer and tumor-promoting effects. Whether dietary fatty acids are associated with colorectal cancer (CRC) in humans remains inconclusive. We investigated associations between dietary fatty acids and risk of CRC among 59 986 men who participated in the Shanghai Men's Health Study (SMHS), an ongoing population-based prospective cohort study. We identified 876 incident CRC cases in the SMHS during a mean follow-up of 9.8 years. Associations between dietary fatty acid intake and CRC risk were evaluated by Cox proportional hazard regression analyses. Consumption of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) was not significantly associated with CRC risk. Multivariate hazard ratios (HRs) and respective 95% confidence intervals (CIs) for Quartile 4 vs Quartile 1 were 0.92 (0.74-1.14; Ptrend = 0.47) for SFA, 0.95 (0.79-1.16; Ptrend = 0.74) for MUFA and 1.18 (0.95-1.46; Ptrend = 0.21) for PUFA. No significant associations were found for total n-6 PUFA or total n-3 PUFA. Additionally, we performed a meta-analysis to summarize results from the present study and 28 reports from 26 additional cohorts, which supported the overall null association between dietary fatty acid intake and CRC risk among men. Docosahexanoic acid and eicosapentaenoic acid were associated with 11% to 12% reduced risk, and linoleic acid a 19% increased risk, of CRC in the meta-analysis of combined sexes. In conclusion, this population-based prospective study and meta-analysis of cohort studies found little evidence that dietary fatty acid intake was associated with risk of CRC in men.

Explaining the link between adiposity and colorectal cancer risk in men and postmenopausal women in the UK Biobank: A sequential causal mediation analysis.

Mechanisms underlying adiposity-colorectal cancer (CRC) association are incompletely understood. Using UK Biobank data, we investigated the role of C-reactive protein (CRP), hemoglobin-A1c (HbA1c) and (jointly) sex hormone-binding globulin (SHBG) and testosterone, in explaining this association. Total effect of obesity versus normal-weight (based on waist circumference, body mass index, waist-hip ratio) on CRC risk was decomposed into natural direct (NDE) and indirect (NIE) effects using sequential mediation analysis. After a median follow-up of 7.1 years, 2070 incident CRC cases (men = 1,280; postmenopausal women = 790) were recorded. For men, the adjusted risk ratio (RR) for waist circumference (≥102 vs. ≤94 cm) was 1.37 (95% confidence interval [CI], 1.19-1.58). The RRsNIE were 1.08 (95% CI: 1.01-1.16) through all biomarkers, 1.06 (95% CI: 1.01-1.11) through pathways influenced by CRP, 0.99 (95% CI: 0.97-1.01) through HbA1c beyond (the potential influence of) CRP and 1.03 (95% CI: 0.99-1.08) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.26 (95% CI: 1.09-1.47). For women, the RR for waist circumference (≥88 vs. ≤80 cm) was 1.27 (95% CI: 1.07-1.50). The RRsNIE were 1.08 (95% CI: 0.94-1.22) through all biomarkers, 1.08 (95% CI: 0.99-1.17) through CRP, 1.00 (95% CI: 0.98-1.02) through HbA1c beyond CRP and 1.00 (95% CI: 0.92-1.09) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.18 (95% CI: 0.96-1.45). For men and women, pathways influenced by CRP explained a small proportion of the adiposity-CRC association. Testosterone and SHBG also explained a small proportion of this association in men. These results suggest that pathways marked by these obesity-related factors may not explain a large proportion of the adiposity-CRC association.

Estimation of Absolute Risk of Colorectal Cancer Based on Healthy Lifestyle, Genetic Risk, and Colonoscopy Status in a Population-Based Study

Estimates of absolute risk of colorectal cancer (CRC) are needed to facilitate communication and better inform the public about the potentials and limits of cancer prevention. Using data from a large population-based case-control study in Germany (Darmkrebs: Chancen der Verhütung durch Screening [DACHS] study, which began in 2003) and population registry data, we calculated 30-year absolute risk estimates for development of CRC based on a healthy lifestyle score (derived from 5 modifiable lifestyle factors: smoking, alcohol consumption, diet, physical activity, and body fatness), a polygenic risk score (based on 90 single-nucleotide polymorphisms), and colonoscopy history. We analyzed data from 4220 patients with CRC and 3338 individuals without CRC. Adherence to a healthy lifestyle and colonoscopy in the preceding 10 years were associated with a reduced relative risk of CRC in men and women. We observed a higher CRC risk in participants with high or intermediate genetic risk scores. For 50-year-old men and women without a colonoscopy, the absolute risk of CRC varied according to the polygenic risk score and the healthy lifestyle score (men, 3.5%-13.4%; women, 2.5%-10.6%). For 50-year-old men and women with a colonoscopy, the absolute risk of developing CRC was much lower but still varied according to the polygenic risk score and the healthy lifestyle score (men, 1.2%-4.8%; women, 0.9%-4.2%). Among all risk factor profiles, the 30-year absolute risk estimates consistently decreased with adherence to a healthy lifestyle. In a population-based study, we found that a colonoscopy can drastically reduce the absolute risk of CRC and that the genetically predetermined risk of CRC can be further reduced by adherence to a healthy lifestyle. Our results show the magnitude of CRC prevention possible through colonoscopy and lifestyle at a predefined genetic risk. This observational study has been registered in the German Clinical Trials Register (DRKS00011793), which is a primary registry in the World Health Organization Registry Network.

Adherence to the World Cancer Research Fund/American Institute for Cancer Research 2018 Recommendations for Cancer Prevention and Risk of Colorectal Cancer.

The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) 2018 diet, nutrition, and physical activity recommendations aim to reduce cancer risk. We examined adherence to the WCRF/AICR recommendations and colorectal cancer risk in two prospective cohorts. We followed 68,977 women in the Nurses' Health Study and 45,442 men in the Health Professionals Follow-up Study from 1986 until 2012. We created cumulatively averaged WCRF/AICR scores using updated diet, adiposity, and physical activity data from questionnaires, and used Cox regression to estimate sex-specific HRs and 95% confidence intervals (CI) for incident colorectal cancer. We documented 2,449 colorectal cancer cases. Men in the highest quintile of the WCRF/AICR lifestyle score had a lower risk of colorectal cancer compared with those in the lowest quintile (HRQ5vsQ1 = 0.64; 95% CI, 0.52-0.77). The result was weaker in women (HRQ5vsQ1 = 0.86; 95% CI, 0.72-1.02; P heterogeneity by sex = 0.006). When analyzing the diet recommendations alone, we similarly observed stronger inverse associations in men (HRQ5vsQ1 = 0.74; 95% CI, 0.61-0.90) compared with women (HRQ5vsQ1 = 0.93; 95% CI, 0.77-1.12; P heterogeneity by sex = 0.06). In men, the lifestyle score was more strongly inversely associated with risk of distal colon cancer compared with proximal colon or rectal cancer (P common effects = 0.03); we did not observe significant differences between anatomic locations in women. The 2018 WCRF/AICR cancer prevention recommendations are associated with lower colorectal cancer risk in men, with weaker results in women. Consideration of adiposity and physical activity in conjunction with diet is important for colorectal cancer prevention.

Cruciferous vegetable intake and colorectal cancer risk: Japan public health center-based prospective study.

We aimed to assess the association between cruciferous vegetable intake and colorectal cancer (CRC) development among Japanese adults aged between 45 and 74 years in the Japan Public Health Center-based Prospective Study. During 1 325 853 person-years of follow-up, 2612 CRC cases were identified. The association of cruciferous vegetable intake with CRC risk was assessed using a Cox proportional hazard regression model to compute hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. No significant association was observed between the highest cruciferous vegetable intake quartile (compared with the lowest) and CRC risk in men (multivariate HRs: 1.08; 95% CI: 0.91, 1.29) and women (multivariate HRs: 0.99; 95% CI: 0.80, 1.22) and its subsites. Women showed a marginal negative association between cruciferous vegetable intake and the risk of colon cancer (CC) after excluding participants who developed CC in the first 3 years of follow-up (P for trend = 0.08); a positive association was found with proximal CC in men. Cruciferous vegetable intake does not have a significant association with CRC risk in the Japanese general population.

Dietary intake of fiber, whole grains and risk of colorectal cancer: An updated analysis according to food sources, tumor location and molecular subtypes in two large US cohorts.

Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are limited on different food sources of fiber and heterogeneity by tumor subsite and molecular profile. We prospectively followed for CRC incidence 90,869 women from the Nurses' Health Study (1980-2012) and 47,924 men from the Health Professionals Follow-up Study (1986-2012), who completed a validated food frequency questionnaire every 4 years. Cox proportional hazards regression was used to examine the associations with CRC risk for total, cereal, fruit and vegetable fiber and whole grains. We also assessed the associations according to tumor subsites (proximal colon, distal colon and rectum) and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype and KRAS mutation). We documented 3,178 CRC cases during 3,685,903 person-years of follow-up in the NHS and HPFS. Intake of total dietary fiber was not associated with CRC risk after multivariable adjustment in either women (hazard ratio [HR] comparing extreme deciles, 1.17; 95% CI, 0.92-1.48, ptrend = 0.55) or men (HR, 0.90; 95% CI, 0.67-1.21, ptrend = 0.47). Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men with an HR of 0.75 (95% CI, 0.57-1.00) and 0.72 (95% CI, 0.54-0.96), respectively. No heterogeneity was detected by tumor subsite or molecular markers (pheterogeneity > 0.05). Higher intake of total dietary fiber within the range of a typical American diet is unlikely to substantially reduce CRC risk. The potential benefit of cereal fiber and whole grains in men warrants further confirmation.

Use of Phosphodiesterase 5 Inhibitors Is Associated With Lower Risk of Colorectal Cancer in Men With Benign Colorectal Neoplasms

Phosphodiesterase 5 (PDE5) inhibitors have been proposed to have chemopreventative effects on colorectal cancer (CRC), although data are needed from population-based studies. We performed a nationwide cohort study to investigate the association between the use of PDE5 inhibitors and the risk of CRC in men with benign colorectal neoplasms. We identified men who received a diagnosis of benign colorectal neoplasm from July 2005 through March 2015 who were listed in the Swedish Hospital Discharge Register. We linked data with those from other national Swedish registers to obtain information about the prescription of PDE5 inhibitors and CRC diagnoses. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 4823 patients were prescribed PDE5 inhibitors during the study period; the incidence rate of CRC was 2.64 per 1000 person-years for men prescribed PDE5 inhibitors compared with 4.46 per 1000 person-years for men without a prescription. We found a significant negative association between PDE5 inhibitor use and risk of CRC (adjusted HR, 0.65; 95% CI, 0.49-0.85); the decreased risk of CRC was associated with an increased cumulative dose of PDE5 inhibitors (P= .003). PDE5 prescription was associated with greater reduction in risk of advanced-stage CRC (adjusted HR, 0.61; 95% CI, 0.37-1.00) than early-stage CRC (adjusted HR, 0.70; 95% CI, 0.50-0.98), but the difference was not significant. In a nationwide population-based study of men with a diagnosis of benign colorectal neoplasm in Sweden, we found evidence that use of PDE5 inhibitors is associated with a reduced risk of CRC. Further studies are needed to confirm the observed association.

Recommendation-based dietary indexes and risk of colorectal cancer in the Nurses’ Health Study and Health Professionals Follow-up Study

Many dietary indexes exist for chronic disease prevention, but the optimal dietary pattern for colorectal cancer prevention is unknown. We sought to determine associations between adherence to various dietary indexes and incident colorectal cancer in 2 prospective cohort studies. We followed 78,012 women in the Nurses' Health Study and 46,695 men in the Health Professionals Follow-up Study from 1986 and 1988, respectively, until 2012. We created dietary index scores for the Dietary Approaches to Stop Hypertension (DASH) diet, Alternative Mediterranean Diet (AMED), and Alternative Healthy Eating Index-2010 (AHEI-2010) and used Cox regression to estimate HRs and 95% CIs for risk of colorectal cancer (CRC) and by anatomic subsite. We also conducted latency analyses to examine associations between diet and CRC risk during different windows of exposure. We conducted analyses in men and women separately, and subsequently pooled these results in a random-effects meta-analysis. We documented 2690 colorectal cancer cases. Pooled multivariable HRs for colorectal cancer risk comparing the highest to lowest quintile of diet scores were 0.89 (95% CI: 0.74, 1.08; P-trend= 0.10) for DASH, 0.89 (95% CI: 0.73, 1.10; P-trend= 0.31) for AMED, and 0.95 (95% CI: 0.83, 1.09; P-trend= 0.56) for AHEI-2010 (P-heterogeneity ≥ 0.07 for all). In sex-specific analyses, we observed stronger associations in men for all dietary indexes (DASH: multivariable HR= 0.81, 95% CI: 0.66, 0.98; P-trend= 0.003; AMED: multivariable HR= 0.80, 95% CI: 0.65, 0.98; P-trend= 0.02; AHEI-2010: multivariable HR= 0.88, 95% CI: 0.72, 1.07; P-trend= 0.04) than in women (multivariable HRs range from 0.98 to 1.01). Adherence to the DASH, AMED, and AHEI-2010 diets was inversely associated with colorectal cancer risk in men. These diets were not associated with colorectal cancer risk in women. This observational study was registered at http://www.clinicaltrials.gov as NCT03364582.

Sex-Specific Association between Family History of Diabetes and Risk of Colorectal Cancer: Two Prospective Cohort Studies.

Type 2 diabetes (T2D) is associated with increased risk of colorectal cancer. It remains unclear whether family history of diabetes influences colorectal cancer risk and relevant biomarkers. We followed 101,323 women from the Nurses' Health Study (1982-2012) and 48,542 men from the Health Professionals Follow-up Study (1988-2012), free of cancer and inflammatory bowel disease at baseline. Participants reported whether any of their first-degree family members ever had diabetes in multiple questionnaires administered biennially. Plasma levels of colorectal cancer-related biomarkers were measured in subsets of participants from previous nested case-control studies. We documented 1,950 colorectal cancer cases in women and 1,173 colorectal cancer cases in men. After adjustment for potential confounders including obesity and diabetes, the hazard ratio (HR) for colorectal cancer among men who had family history of diabetes was 1.19 [95% confidence interval (CI), 1.04-1.36) as compared with those who did not. The corresponding HR was 1.06 among women (95% CI, 0.96-1.17). Interestingly, for individuals younger than 60 years, these associations appeared stronger among men (HR, 1.65; 95% CI, 1.15-2.38) and possibly among women (HR, 1.23; 95% CI, 0.99-1.54). Moreover, family history of diabetes was related to reduced levels of estradiol, sex hormone binding globulin (SHBG), and adiponectin in men, with a greater reduction of SHBG for those younger than 60 years (P for interaction = 0.03). In conclusion, family history of diabetes was associated with increased colorectal cancer risk in men, which may be partly mediated by altered sex hormones and adiponectin. The possible positive association in younger women needs further confirmation. Cancer Prev Res; 11(9); 535-44. ©2018 AACR.

Association of dietary insulinemic potential and colorectal cancer risk in men and women

Insulin response may be important in colorectal cancer development. Diet modulates insulin response and may be a modifiable factor in colorectal cancer prevention. We examined associations between hyperinsulinemic diets and colorectal cancer risk with the use of an empirical dietary index for hyperinsulinemia (EDIH), a food-based index that characterizes dietary insulinemic potential on the basis of circulating C-peptide concentrations. Diet was assessed every 4 y with food-frequency questionnaires in 46,210 men (Health Professionals Follow-Up Study, 1986-2012) and 74,191 women (Nurses' Health Study, 1984-2012) to calculate EDIH scores. Multivariable-adjusted Cox regression was used to calculate HRs and 95% CIs for colorectal, proximal/distal colon, and rectal cancer risk. During 26 y of follow-up, we documented 2683 incident colorectal cancer cases. Comparing participants in the highest with those in the lowest quintiles, higher EDIH scores were associated with 33% (men: HR: 1.33; 95% CI: 1.11, 1.61; P-trend=0.0005), 22% (women: HR: 1.22; 95% CI: 1.03, 1.45; P-trend=0.01), and 26% (men and women: pooled HR: 1.26; 95% CI: 1.12, 1.42; P-trend <0.0001) higher risk of developing colorectal cancer. The positive associations were limited to the distal colon and rectum in men and to the distal and proximal colon in women; however, combined risk estimates were significant for all anatomic locations except for the rectum. For example, comparing participants in extreme EDIH quintiles, there was no significant association for proximal colon cancer in men (HR: 1.15; 95% CI: 0.84, 1.57; P-trend=0.32), but the risk was elevated for distal colon (HR: 1.63; 95% CI: 1.14, 2.32; P-trend=0.002) and rectal (HR: 1.63; 95% CI: 1.09, 2.44; P-trend=0.01) cancer. Among women, the risk was elevated for proximal (HR: 1.28; 95% CI: 1.00, 1.63; P-trend=0.03) and distal (HR: 1.46; 95% CI: 1.05, 2.03; P-trend=0.03) colon cancer but not for rectal cancer (HR: 0.88; 95% CI: 0.60, 1.29; P-trend=0.61). The findings suggest that the insulinemic potential of diet may partly underlie the influence of dietary intake on colorectal cancer development. This observational study was registered at www.clinicaltrials.gov as NCT03364582.

PO-063 Pre-diagnostic unconjugated bilirubin levels and colorectal cancer risk in the european prospective investigation into cancer and nutrition (EPIC)

IntroductionUnconjugated Bilirubin (UCB), the end product of heme catabolism, is a powerful antioxidant. A mild chronic elevation of circulating UCB, known as Gilbert’s Syndrome (GS), is a relatively common condition affecting 5%–10% (depending on ethnicity and gender) of the adult population. Individuals with endogenously elevated UCB appear to be at lower risk of developing certain diseases where oxidative stress has been implicated in the disease process, such as cancer.Material and methodsWe investigated the association between pre-diagnostic plasma UCB concentrations and risk of colorectal cancer (CRC) development in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, a multicenter prospective study carried out in 23 centres from 10 European countries including 5 19 978 participants.Plasma UCB was measured by High Performance Liquid Chromatography (HPLC) in 1387 cases and 1387 controls matched on age, centre, follow-up time, time of blood collection, fasting status and menopausal status in women.Odds ratios (OR) and 95% confidence intervals (CI) for CRC risk were estimated using multivariable conditional logistic regression models stratified by sex, which were adjusted for potential confounders. UCB was Log2- transformed when used as a continuous variable to improve linearity.Results and discussionsIn a multivariable model that included potential confounding factors, higher Log2- transformed UCB, corresponding to a doubling of UCB concentration, was associated with increased CRC risk in men (OR=1.27; 95% CI: 1.05,1.52; p=0.01) whereas an inverse association with CRC risk was observed in women (OR=0.83; 95% CI: 0.70,0.99; p=0.04).ConclusionThese results suggest that higher levels of circulating UCB may confer protection against CRC in women but may elevate risk in men. Additional studies are necessary to confirm these findings and to further investigate potential underlying mechanisms for the role of circulating UCB in CRC development.