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

Background: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer.Methods: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients).Results: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women.Conclusions: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: Antibiotics use may increase colorectal cancer (CRC) risk by altering the gut microbiota, with suggestive evidence reported. Our study aims to investigate antibiotics use in relation to subsequent CRC risk.Methods: This is a nationwide, population-based study with a matched case-control design (first primary CRC cases and 5 matched, cancer-free controls). Complete-population data, extracted from Swedish national registers for the period 2005-2016, were used to calculate odds ratios and 95% confidence intervals.Results: We included 40 545 CRC cases and 202 720 controls. Using the full dataset, we found a positive association between more frequent antibiotics use and CRC, excluding antibiotics prescribed within 2 years of diagnosis attenuated results toward the null. In site-specific analyses, excluding the 2-year washout, the positive association was confined to the proximal colon (adjusted odds ratio for very high use vs no use = 1.17, 95% confidence interval = 1.05 to 1.31). For rectal cancer, an inverse association, which appears to be driven by women, was observed. Quinolones and sulfonamides and/or trimethoprims were positively associated with proximal colon cancer, whereas a more general inverse association, across antibiotics classes, was observed for rectal cancer. We found no association between methenamine hippurate, a urinary tract antiseptic not affecting the gut microbiota, and CRC risk.Conclusions: This register-based study covering the entire population of Sweden found a robust association between antibiotics use and higher risk of proximal colon cancer and an inverse association with rectal cancer in women. This study strengthens the evidence from previous investigations and adds important insight into site-specific colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Background Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results. Methods We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone–binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided. Results In the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log2 1-unit increment   =   1.17 [95% confidence interval   =   1.00 to 1.38]; odds ratioquartile4-quartile1   =   1.33 [95% confidence interval   =   0.89 to 1.97], P trend   =  .20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk. Conclusion Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies, but current evidence on smoking in association with survival after CRC diagnosis is limited. Methods We pooled data from 12 345 patients with stage I-IV CRC from 11 epidemiologic studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of prediagnostic smoking behavior with overall, CRC-specific, and non-CRC-specific survival. Results Among 12 345 patients with CRC, 4379 (35.5%) died (2515 from CRC) over a median follow-up time of 7.5 years. Smoking was strongly associated with worse survival in stage I-III patients, whereas no association was observed among stage IV patients. Among stage I-III patients, clear dose-response relationships with all survival outcomes were seen for current smokers. For example, current smokers with 40 or more pack-years had statistically significantly worse overall, CRC-specific, and non-CRC-specific survival compared with never smokers (hazard ratio [HR] =1.94, 95% confidence interval [CI] =1.68 to 2.25; HR = 1.41, 95% CI = 1.12 to 1.78; and HR = 2.67, 95% CI = 2.19 to 3.26, respectively). Similar associations with all survival outcomes were observed for former smokers who had quit for less than 10 years, but only a weak association with non-CRC-specific survival was seen among former smokers who had quit for more than 10 years. Conclusions This large consortium of CRC patient studies provides compelling evidence that smoking is strongly associated with worse survival of stage I-III CRC patients in a clear dose-response manner. The detrimental effect of smoking was primarily related to noncolorectal cancer events, but current heavy smoking also showed an association with CRC-specific survival. [ABSTRACT FROM AUTHOR]

Background: Although carbohydrate reduction of varying degrees is a popular and controversial dietary trend, potential long-term effects for health, and cancer in specific, are largely unknown.Methods: We studied a previously established low-carbohydrate, high-protein (LCHP) score in relation to the incidence of cancer and specific cancer types in a population-based cohort in northern Sweden. Participants were 62,582 men and women with up to 17.8 years of follow-up (median 9.7), including 3,059 prospective cancer cases. Cox regression analyses were performed for a LCHP score based on the sum of energy-adjusted deciles of carbohydrate (descending) and protein (ascending) intake labeled 1 to 10, with higher scores representing a diet lower in carbohydrates and higher in protein. Important potential confounders were accounted for, and the role of metabolic risk profile, macronutrient quality including saturated fat intake, and adequacy of energy intake reporting was explored.Results: For the lowest to highest LCHP scores, 2 to 20, carbohydrate intakes ranged from median 60.9 to 38.9% of total energy intake. Both protein (primarily animal sources) and particularly fat (both saturated and unsaturated) intakes increased with increasing LCHP scores. LCHP score was not related to cancer risk, except for a non-dose-dependent, positive association for respiratory tract cancer that was statistically significant in men. The multivariate hazard ratio for medium (9-13) versus low (2-8) LCHP scores was 1.84 (95% confidence interval: 1.05-3.23; p-trend = 0.38). Other analyses were largely consistent with the main results, although LCHP score was associated with colorectal cancer risk inversely in women with high saturated fat intakes, and positively in men with higher LCHP scores based on vegetable protein.Conclusion: These largely null results provide important information concerning the long-term safety of moderate carbohydrate reduction and consequent increases in protein and, in this cohort, especially fat intakes. In order to determine the effects of stricter carbohydrate restriction, further studies encompassing a wider range of macronutrient intakes are warranted. [ABSTRACT FROM AUTHOR]