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The influence of polyunsaturated fatty acids (PUFAs) on risk of colorectal cancer precursors remains largely unknown. We examined the associations of erythrocyte PUFAs, including n−3 and n−6 PUFAs, with risk of colorectal conventional adenomas and serrated polyps in 4517 participants from three US prospective cohorts who had provided a blood sample and undergone at least one endoscopic examination. We calculated the multivariable odds ratios (ORs) per 1 SD increment in individual PUFAs and the ratio of n−6/n−3 PUFAs. We considered P <.005 statistically significant to account for multiple testing. During a median of 20 years of follow‐up, we documented 493 conventional adenomas and 316 serrated polyps. After adjusting for various CRC risk factors, no associations for PUFAs achieved the stringent statistical significance for either conventional adenomas or serrated polyps (ORs per 1 SD ranged from 0.90 to 1.14). Some associations achieved nominal significance (P <.05), including the association of dihomogammalinolenic acid (DGLA) (20:3, n−6) with lower risk of conventional adenomas (OR = 0.91; 95% confidence interval [CI] = 0.83‐1.00), total n−6 PUFAs with higher risk of proximal serrated polyps (OR = 1.32; 95% CI = 1.01‐1.74) and eicosadienoic acid (20:2, n−6) and DGLA with lower risk of advanced adenomas (OR = 0.83; 95% CI = 0.71‐0.97 and OR = 0.84; 95% CI = 0.72‐0.98, respectively). Our findings indicate that erythrocyte PUFAs in a typical American diet are unlikely to have a substantial influence on risk of colorectal cancer precursors. The subgroup associations require further confirmation. What's new? The influence of polyunsaturated fatty acids on risk of colorectal cancer precursors remains largely unknown. Over a median follow‐up duration of 20 years, this prospective study examined the associations of erythrocyte n‐3 and n‐6 polyunsaturated fatty acids with risk of colorectal cancer precursors in three large prospective cohorts in the United States. No statistically significant association was found at α=0.005 level for any of the fatty acids with either conventional adenomas or serrated polyps. The findings indicate that n‐3 and n‐6 polyunsaturated fatty acids in a typical American diet are unlikely to have a substantial impact on colorectal cancer precursors. [ABSTRACT FROM AUTHOR]

Anthropometric measurements, such as body mass index (BMI), waist circumference, and body fat percentage, have been used as indicators of obesity. Despite evidence that excess body fat is a risk factor for colorectal carcinoma (CRC), the magnitude of the association of BMI and other obesity indicators with the long‐term risk of CRC remains unclear. Utilizing a Cox proportional hazards regression model, we examined differential associations between predicted body fat percentage and BMI with the risk of CRC (n = 2,017). The associations between CRC incidence and different adiposity measurements were also assessed. Predicted body fat percentage had a similar increased risk of CRC risk as BMI. In multivariable‐adjusted analyses, the hazard ratio for CRC in the second to fifth quintiles (compared to the first quintile) of predicted body fat percentage were 1.32, 1.31, 1.53 and 2.09 for men (ptrend < 0.001) and 0.91, 0.90, 0.98 and 1.15 for women (ptrend = 0.03). Among various anthropometric measurements, predicted fat mass and waist circumference were slightly more strongly associated with CRC risk than BMI. In conclusion, the novel anthropometric prediction equations provided further evidence that a greater amount of body fat might contribute to CRC risk in both sexes. An innovative approach enabled us to estimate the susceptibilities of specific body composition with CRC risk, in an inexpensive and minimally invasive manner. Furthermore, the typically used measures of BMI and waist circumference are robust measures of adiposity to predict cancer risk in a relatively healthy population. What's new? While excess body fat is linked to increased colorectal cancer (CRC) risk, the degree to which specific factors, such as body mass index (BMI) and waist circumference, predict long‐term CRC risk is unclear. In this investigation, data from two U.S. prospective cohorts and novel anthropometric prediction equations highly correlated with dual‐energy X‐ray absorptiometry measures were used to examine the long‐term influence of specific body composition on CRC risk. Analyses show that predicted body fat percentage and BMI share similar associations with CRC risk in both sexes. Hence, no marked heterogeneity was observed in CRC risk estimation across adiposity measures. [ABSTRACT FROM AUTHOR]

Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAAs), including leucine, isoleucine and valine, may potentially influence cancer progression by various mechanisms including its role in insulin resistance. However, the association of BCAAs with survival among patients with established colorectal cancer (CRC) remains unclear. We evaluated the associations between postdiagnostic BCAA intake with CRC-specific mortality and overall mortality among 1674 patients with nonmetastatic CRC in the Nurses' Health Study and the Health Professionals Follow-up Study. Patients completed a validated food frequency questionnaire. Multivariable hazard ratios (HRs) were calculated using Cox proportional-hazards regression model after adjustment for tumor characteristics and potential confounding factors. Comparing the highest with the lowest quartile intake of postdiagnostic total BCAA, the multivariable HRs were 1.18 (95% confidence interval [CI], 0.75-1.85, P for trend = .46 across quartiles) for CRC-specific mortality and 1.30 (95% CI, 1.01-1.69, P for trend = .04) for all-cause mortality. The multivariable HRs (the highest vs the lowest quartile) for all-cause mortality were 1.33 (95% CI, 1.03-1.73, P trend = .02) for valine, 1.28 (95% CI, 0.99-1.66, P for trend = .05) for leucine and 1.25 (95% CI, 0.96-1.61, P for trend = .06) for isoleucine. No statistically significant associations with each of the BCAA intake were observed for CRC-specific mortality (all P for trend > .30). Our findings suggest positive associations between higher intake of dietary BCAAs and risk of all-cause mortality in CRC patients. These findings need to be confirmed and potential mechanisms underlying this association need to be elucidated., (© 2020 UICC.)

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10 -6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10 -6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10 -6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis., (© 2019 UICC.)

Alterations in the Wnt/beta-catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin-dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for beta-catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including beta-catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase-2 (COX-2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with beta-catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer-specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03-2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18-3.56; p = 0.011) that was adjusted for potential confounders including beta-catenin, COX-2, FASN, LINE-1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and beta-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.