Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature.

BACKGROUND: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88. METHODS: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases). RESULTS: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066). CONCLUSIONS: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. IMPACT: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study.

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer. IMPACT: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer.

BACKGROUND: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. METHODS: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. RESULTS: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). CONCLUSIONS: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.

Endogenous sex steroid hormones and risk of liver cancer among US men: Results from the Liver Cancer Pooling Project.

Background & Aims: Incidence rates of liver cancer in most populations are two to three times higher among men than women. The higher rates among men have led to the suggestion that androgens are related to increased risk whereas oestrogens are related to decreased risk. This hypothesis was investigated in the present study via a nested case-control analysis of pre-diagnostic sex steroid hormone levels among men in five US cohorts. Methods: Concentrations of sex steroid hormones and sex hormone-binding globulin were quantitated using gas chromatography-mass spectrometry and a competitive electrochemiluminescence immunoassay, respectively. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs for associations between hormones and liver cancer among 275 men who subsequently developed liver cancer and 768 comparison men. Results: Higher concentrations of total testosterone (OR per one-unit increase in log2 = 1.77, 95% CI = 1.38-2.29), dihydrotestosterone (OR = 1.76, 95% CI = 1.21-2.57), oestrone (OR = 1.74, 95% CI = 1.08-2.79), total oestradiol (OR = 1.58, 95% CI=1.22-20.05), and sex hormone-binding globulin (OR = 1.63, 95% CI = 1.27-2.11) were associated with increased risk. Higher concentrations of dehydroepiandrosterone (DHEA), however, were associated with a 53% decreased risk (OR = 0.47, 95% CI = 0.33-0.68). Conclusions: Higher concentrations of both androgens (testosterone, dihydrotestosterone) and their aromatised oestrogenic metabolites (oestrone, oestradiol) were observed among men who subsequently developed liver cancer compared with men who did not. As DHEA is an adrenal precursor of both androgens and oestrogens, these results may suggest that a lower capacity to convert DHEA to androgens, and their subsequent conversion to oestrogens, confers a lower risk of liver cancer, whereas a greater capacity to convert DHEA confers a greater risk. Impact and implications: This study does not fully support the current hormone hypothesis as both androgen and oestrogen levels were associated with increased risk of liver cancer among men. The study also found that higher DHEA levels were associated with lower risk, thus suggesting the hypothesis that greater capacity to convert DHEA could be associated with increased liver cancer risk among men.

Grain, Gluten, and Dietary Fiber Intake Influence Gut Microbial Diversity: Data from the Food and Microbiome Longitudinal Investigation.

Although short-term feeding studies demonstrated effects of grains, fiber, and gluten on gut microbiome composition, the impact of habitual intake of these dietary factors is poorly understood. We examined whether habitual intakes of whole and refined grains, fiber, and gluten are associated with gut microbiota in a cross-sectional study. This study included 779 participants from the multi-ethnic Food and Microbiome Longitudinal Investigation study. Bacterial 16SV4 rRNA gene from baseline stool was amplified and sequenced using Illumina MiSeq. Read clustering and taxonomic assignment was performed using QIIME2. Usual dietary intake was assessed by a 137-item food frequency questionnaire. Association of diet with gut microbiota was assessed with respect to overall composition and specific taxon abundances. Whole grain intake was associated with overall composition, as measured by the Jensen-Shannon divergence (multivariable-adjusted P trend for quartiles = 0.03). The highest intake quartile was associated with higher abundance of Bacteroides plebeius, Faecalibacterium prausnitzii, Blautia producta, and Erysipelotrichaceae and lower abundance of Bacteroides uniformis. These bacteria also varied by dietary fiber intake. Higher refined grain and gluten intake was associated with lower Shannon diversity (P trend < 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity. Significance: Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.

Change in Diet Quality and Meal Sources during the COVID-19 Pandemic in a Diverse Subset of Men and Women in the Cancer Prevention Study-3.

The COVID-19 pandemic resulted in restrictive measures that caused disruptions in behaviors that may have long-term consequences on diet, health, and chronic disease risk. The aim of this study was to assess longitudinal changes in diet quality from before to during the pandemic among 2335 adult participants (816 males and 1519 females; aged 36-78) of the Cancer Prevention Study-3 cohort. We compared dietary screeners conducted in 2018 and 2020 and calculated a diet quality score, which assigned higher points for recommended foods. Overall diet quality slightly improved among all participants from before to during the pandemic, particularly among males (+0.45 points, p < 0.001), White participants (+0.24 points, p < 0.001), and participants reporting weight loss (+0.66 points, p < 0.001 for 2.25 -< 4.5 kg loss; +1.04 points, p < 0.001 for ≥4.5 kg loss); change in diet quality did not differ by other sociodemographic factors. Reported consumption of most food groups decreased, especially whole grains (-0.17 servings/day, p < 0.001) and vegetables (-0.21 servings/day, p < 0.001), primarily among females, Black participants, and participants who gained ≥2.25 kg. The frequency of meals from outside the home decreased, especially in full-service restaurants (-0.47 times/week, p < 0.001) and for ready-to-eat meals (-0.37 times/week, p < 0.001). Declines in whole grain and vegetable consumption raise concerns for weight gain in these populations and increased risk of poor metabolic health and chronic disease.

Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Consistent and changing consumption of fast-food and full-service meals and 3-year weight change in a large population cohort study.

BACKGROUND: An average American consumes 3 meals weekly from fast-food or full-service restaurants, which contain more calories, fat, sodium, and cholesterol than meals prepared at home. OBJECTIVES: This study examined whether consistent and changing fast-food or full-service consumption was associated with weight change over a 3-y period. METHODS: Among 98,589 US adults from the American Cancer Society's Cancer Prevention Study-3, self-reported weight and fast-food and full-service consumption from 2015 and 2018 were examined using a multivariable-adjusted linear regression analysis to assess the association of consistent and changing consumption on 3-y weight change. RESULTS: Individuals who made no changes to their fast-food or full-service intake over the study period gained weight regardless of consumption frequency, although low consumers gained less weight than high consumers (low fast-food: ß = -1.08; 95% CI: -1.22, -0.93; low full-service: ß = -0.35; 95% CI: -0.50, -0.21; P < 0.001). Decreased fast-food intake during the study period (e.g., from high [>1 meal/wk] to low [≤0.5 meal/wk], high to medium [>0.5 to ≤1 meal/wk], or medium to low) and decreased full-service intake from high (≥1 meal/wk) to low (<1 meal/mo) were significantly associated with weight loss (high-low: ß = -2.77; 95% CI: -3.23, -2.31; high-medium: ß = -1.53; 95% CI: -1.72, -1.33; medium-low: ß = -0.85; 95% CI: -1.06, -0.63; high-low full-service: ß = -0.92; 95% CI: -1.36, -0.49; P < 0.001). Decreased consumption of both fast-food and full-service restaurant meals was associated with greater weight loss than decreasing fast-food alone (both: ß = -1.65; 95% CI: -1.82, -1.37; fast-food only: ß = -0.95; 95% CI: -1.12, -0.79; P < 0.001). CONCLUSIONS: Decreased consumption of fast-food and full-service meals over 3 y, particularly among high consumers at baseline, was associated with weight loss and may be an effective approach to weight loss. Moreover, decreasing both fast-food and full-service meal consumption was associated with a greater weight loss than decreasing only fast-food meal consumption.

Elevated dietary carbohydrate and glycemic intake associate with an altered oral microbial ecosystem in two large U.S. cohorts.

The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 non-diabetic subjects from the NCI-PLCO and ACS-CPSII cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA-sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational MANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and ß-diversity and taxon abundance (adjusting for age, sex, cohort, BMI, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P-value) of <0.05 was considered significant. Oral bacterial α-diversity trended higher in participants in the highest quintiles of carbohydrate intake, with marginally increased richness and Shannon diversity (p-trend=0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (q=0.02) and genus Leptotrichia (q=0.01) and with lesser abundance of an Actinomyces OTU (q=4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (q=0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome.

The Associations of Multivitamin and Antioxidant Use With Mortality Among Women and Men Diagnosed With Colorectal Cancer.

BACKGROUND: Colorectal cancer survivors often use multivitamins and other over-the-counter dietary supplements, but evidence is limited regarding their potential associations with mortality. METHODS: This prospective analysis included women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer-free at baseline (1992 or 1993) and diagnosed with colorectal cancer through June 2015. Detailed information on multivitamin use, vitamin C supplements, and vitamin E supplements was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 3176 and 2006 colorectal cancer survivors, respectively, among whom 2116 (648 from colorectal cancer) and 1256 (242 from colorectal cancer) died. Multivariable-adjusted Cox proportional hazards regression models examined associations. All statistical tests were 2-sided. RESULTS: Among colorectal cancer survivors, 49.7% and 58.5% reported multivitamin use before and after diagnosis, respectively (vitamin C use before and after diagnosis: 27.8% and 28.1%; vitamin E use before and after diagnosis: 27.5% and 29.4%, respectively). There were no statistically significant associations of pre- or postdiagnosis multivitamin use with all-cause, colorectal cancer-specific, or noncolorectal cancer mortality. Vitamin C was also not associated with any mortality outcomes. However, prediagnosis vitamin E use was associated with a non-statistically significant increased risk of all-cause mortality (multivariable adjusted hazard ratio = 1.08, 95% confidence intervals = 0.96 to 1.23) and all other noncolorectal cancer mortality (multivariable adjusted hazard ratio = 1.13, 95% confidence intervals = 0.97 to 1.31). CONCLUSIONS: These results suggest that multivitamin use before or after diagnosis is not associated with mortality in colorectal cancer survivors. However, vitamin E use may be associated with increased risk of mortality and merits further investigation.

Association of Socioeconomic and Geographic Factors With Diet Quality in US Adults.

Importance: Poor diet quality is a key factor associated with obesity and chronic disease. Understanding associations of socioeconomic and geographic factors with diet quality can inform public health and policy efforts for advancing health equity. Objective: To identify socioeconomic and geographic factors associated with diet quality in a large US cohort study. Design, Setting, and Participants: This cross-sectional study included adult men and women who enrolled in the Cancer Prevention Study-3 at American Cancer Society community events in 35 US states, the District of Columbia, and Puerto Rico between 2006 and 2013. Participants completed a validated food frequency questionnaire between 2015 and 2017. Data were analyzed from February to November 2021. Exposures: The main exposures included self-reported race and ethnicity, education, and household income. Geocoded addresses were used to classify urbanization level using Rural-Urban Commuting Area codes; US Department of Agriculture's Food Access Research Atlas database classified residence in food desert. Main Outcomes and Measures: Poor diet quality was defined as lowest quartile of dietary concordance with the 2020 American Cancer Society recommendations for cancer prevention score, based on sex-specific intake categories of vegetables and legumes, whole fruits, whole grains, red and processed meat, highly processed foods and refined grains, and sugar-sweetened beverages. Results: Among 155 331 adults, 123 115 were women (79.3%), and the mean (SD) age was 52 (9.7) years), and there were 1408 American Indian or Alaskan Native individuals (0.9%); 2721 Asian, Native Hawaiian, or Pacific Islander individuals (1.8%); 3829 Black individuals (2.5%); 7967 Hispanic individuals (5.1%); and 138 166 White individuals (88.9%). All key exposures assessed were statistically significantly and independently associated with poor diet quality. Compared with White participants, Black participants had a 16% (95% CI, 8%-25%) higher risk of poor diet quality, while Hispanic/Latino had 16% (95% CI, 12%-21%) lower risk and Asian, Native Hawaiian, and Pacific Islander participants had 33% (95% CI, 26%-40%) lower risk of poor diet quality. After controlling for other characteristics, rural residence was associated with a 61% (95% CI, 48%-75%) higher risk of poor diet quality, and living in a food desert was associated with a 17% (95% CI, 12%-22%) higher risk. Associations of income with diet quality and education with diet quality varied by race and ethnicity (income: P for interaction = .01; education: P for interaction < .001). All diet score components were associated with disparities observed. Conclusions and Relevance: This cross-sectional study found that multiple individual-level socioeconomic and geographic variables were independently associated with poor diet quality among a large, racially and ethnically and geographically diverse US cohort. These findings could help to identify groups at highest risk of outcomes associated with poor diet to inform future approaches for advancing health equity.

Diabetes mellitus in relation to colorectal tumor molecular subtypes: A pooled analysis of more than 9000 cases.

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.

Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. METHODS: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations. RESULTS: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. CONCLUSIONS: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes. IMPACT: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

Association of Emulsifier and Highly Processed Food Intake with Circulating Markers of Intestinal Permeability and Inflammation in the Cancer Prevention Study-3 Diet Assessment Sub-Study.

Compelling animal studies report increased intestinal permeability, inflammation, and colorectal carcinogenesis with exposure to certain emulsifiers commonly added to processed foods, but human data are lacking. Highly processed food consumption is also associated with obesity and higher risk of chronic diseases. We cross-sectionally examined the association of emulsifier and highly processed food consumption estimated from six 24-h dietary recalls among 588 U.S. men and women over one year, with biomarkers of intestinal permeability and inflammation measured from two fasting blood samples collected six months apart. In multivariable-adjusted generalized linear models, greater emulsifier intake (g/d) was not associated with antibodies to flagellin (P-trend = 0.88), lipopolysaccharide (LPS) (P-trend = 0.56), or the combined total thereof (P-trend = 0.65) but was positively associated with an inflammatory biomarker, glycoprotein acetyls (GlycA) (P-trend = 0.02). Highly processed food intake (% kcal/d) was associated with higher anti-LPS antibodies (P-trend = 0.001) and total anti-flagellin and anti-LPS antibodies (P-trend = 0.005) but not with other biomarkers, whereas processed food intake expressed as % g/d was associated with higher GlycA (P-trend = 0.02). Our findings suggest that, broadly, highly processed food consumption may be associated with intestinal permeability biomarkers, and both emulsifier and highly processed food intakes may be associated with inflammation. Additional studies are warranted to further evaluate these relationships.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1957947.

Joint associations of physical activity and body mass index with the risk of established excess body fatness-related cancers among postmenopausal women.

PURPOSE: Excess body fatness and physical activity independently influence the risk of several types of cancer. However, few studies have examined whether physical activity mitigates the excess risk associated with higher body mass index (BMI). METHODS: We examined the individual and joint associations between BMI (kg/m2) and leisure-time moderate-to-vigorous physical activity (MVPA, MET-hours/week) with the risk of three established excess body fatness-related cancers (breast, colon, and endometrial) among 43,795 postmenopausal women in the Cancer Prevention Study II (CPS-II) Nutrition Cohort (1992/1993-2015). Further exclusions for women without an intact uterus resulted in 31,805 women for endometrial cancer analyses. Multivariable Cox proportional hazards regression was used to calculate hazard ratio (HR) and 95% confidence intervals (CIs) with interaction terms to assess multiplicative interaction. The relative excess risk due to interaction (RERI) was calculated to assess additive interaction. RESULTS: BMI and MVPA were individually associated with breast and endometrial cancer risk, but only BMI was associated with colon cancer risk. In joint analyses, increasing levels of MVPA did not lower the risk of these cancers among obese women. For example, compared to the common referent (BMI 18.5- < 25 kg/m2, MVPA > 0- < 7.5 MET-hours/week), BMI ≥ 30 kg/m2 was associated with a higher risk of breast cancer among women with low MVPA (> 0-< 7.5 MET-hours/week: HR = 1.42, 95% CI: 1.22 - 1.67) and high MVPA (≥ 15 MET-hours/week: HR = 1.53, 95% CI: 1.25 - 1.87; RERI = 0.20, 95% CI: -0.14, 0.54, multiplicative Pinteraction = 0.64). CONCLUSION: Our results do not support the hypothesis that leisure-time physical activity mitigates the excess risk associated with higher BMI for risk of breast, endometrial, or colon cancer among postmenopausal women.

Intake of Dietary Fruit, Vegetables, and Fiber and Risk of Colorectal Cancer According to Molecular Subtypes: A Pooled Analysis of 9 Studies.

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF-wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (P trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.