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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 Ptrend 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 (Ptrend < 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.

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 nondiabetic subjects from the NCI Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II 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 multivariate ANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, body mass index, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P value) of Significance: Taxonomic differences at the highest intake quintiles may reflect diet-induced increases in carcinogenic bacteria and decreases in protective bacteria. Genus Leptotrichia has been implicated in cancer and inflammatory disease, while immunostimulatory genus Gemella may increase inflammatory disease risk. These differences further our understanding of possible mechanisms leading to oral and systemic disease.

Sensitivity analyses, alpha diversity

Carbohydrate and GI Pearson correlation

S1. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of dietary fiber intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).S2. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of whole grain intake in the Food and Microbiome Longitudinal Investigation (FAMiLI), stratified by race/ethnicity.S3. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of whole grain intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).S4. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of whole grain intake in the Food and Microbiome Longitudinal Investigation (FAMiLI), excluding participants with self-reported inflammatory bowel disease (N=21) at enrollment.S5. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of refined grain (with sweets/desserts) intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).S6. Gut microbiome alpha- and beta-diversity according to energy-adjusted quartiles of gluten (with sweets/desserts) intake in the Food and Microbiome Longitudinal Investigation (FAMiLI).

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 nondiabetic subjects from the NCI Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II 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 multivariate ANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, body mass index, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P value) of Ptrend = 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 operational taxonomic unit (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.Significance:Taxonomic differences at the highest intake quintiles may reflect diet-induced increases in carcinogenic bacteria and decreases in protective bacteria. Genus Leptotrichia has been implicated in cancer and inflammatory disease, while immunostimulatory genus Gemella may increase inflammatory disease risk. These differences further our understanding of possible mechanisms leading to oral and systemic disease.

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 Ptrend 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 (Ptrend < 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.

Supplementary Table S2

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 (Ptrend 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.

Background and AimsThe microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain ofEscherichia coliharboring thepksisland that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown.MethodsSBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival.ResultsIn total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5×10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1×10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6×10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was theAPC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3×10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88- positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage.ConclusionSBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

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 randomization (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4,043 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, CI(95%): 0.78-0.99,P=0.04; OR: 0.93, CI(95%): 0.88-0.98,P=0.01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, CI(95%): 0.80-0.97,P=0.01] 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, CI(95%): 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, CI(95%): 0.93-0.99,P=0.02] and following adjustment for the other WBC subtypes [RR: 0.96, CI(95%): 0.93-0.99,P=0.001] 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.What is already known of this topicWhile previous observational studies have suggested a protective role for eosinophils in colorectal cancer development and implicated neutrophils, whether changes in the levels of circulating white blood cells causes colorectal cancer has not been explored.What this study addsOur study is the first to use Mendelian randomization (MR) to investigate this relationship. In parallel, for comparison, we also conduct the largest cohort study to date on the topic. We found evidence to suggest that elevated eosinophil and lymphocyte count may have a protective effect on CRC risk, adding new insights into the pathogenesis of CRC.How this study might affect research, practice or policyOur findings will encourage further mechanistic exploration to understand the biological mechanisms underpinning our findings, which may lead to new therapeutic approaches or risk reduction strategies.

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

A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (ORIVW = 0.87, 95% CI = 0.78, 0.97, P = 0.01), but not in women or in both sexes combined. Τhis association remained consistent in some, but not all, sensitivity analyses and was very similar for colon and rectal cancer. There was no evidence of an association for any other sleep trait. Overall, this study provides little to no evidence of an association between genetically predicted sleep traits and CRC risk.

Diabetes is an established risk factor for colorectal cancer; however, the mechanisms underlying this relationship are not fully understood and the role of genetic variation is unclear. We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes and joint testing of Gxdiabetes, G-colorectal cancer association and/or G-diabetes correlation (2,3-degrees of freedom joint tests; d.f.). Based on the joint tests, variant rs3802177 inSLC30A8(p-value3-d.f.:5.46×10−11; regulates phosphorylation of the insulin receptor and phosphatidylinositol-3 kinase activity) and rs9526201 inLRCH1(p-value2-d.f.:7.84×10−09; regulates T cell migration and Natural Killer Cell cytotoxicity) were associated with colorectal cancer. These results suggest that variation in genes related to insulin signalling and immune function may modify the association of diabetes with colorectal cancer and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

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.To identify socioeconomic and geographic factors associated with diet quality in a large US cohort study.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.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.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.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.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.

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.

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). 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. 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– 0– 0–

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.

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.

Objective:Consumption of cow’s milk, which is associated with diet and health benefits, has decreased in the USA. The simultaneous increase in demand for more costly organic milk suggests consumer concern about exposure to production-related contaminants may be contributing to this decline. We sought to determine if contaminant levels differ by the production method used.Design:Half-gallon containers of organic and conventional milk (four each) were collected by volunteers in each of nine US regions and shipped on ice for analysis. Pesticide, antibiotic and hormone (bovine growth hormone (bGH), bGH-associated insulin-like growth factor 1 (IGF-1)) residues were measured using liquid or gas chromatography coupled to mass or tandem mass spectrometry. Levels were compared against established federal limits and by production method.Setting:Laboratory analysis of retail milk samples.Results:Current-use pesticides (5/15 tested) and antibiotics (5/13 tested) were detected in several conventional (26–60 %; n 35) but not in organic (n 34) samples. Among the conventional samples, residue levels exceeded federal limits for amoxicillin in one sample (3 %) and in multiple samples for sulfamethazine (37 %) and sulfathiazole (26 %). Median bGH and IGF-1 concentrations in conventional milk were 9·8 and 3·5 ng/ml, respectively, twenty and three times that in organic samples (P < 0·0001).Conclusions:Current-use antibiotics and pesticides were undetectable in organic but prevalent in conventionally produced milk samples, with multiple samples exceeding federal limits. Higher bGH and IGF-1 levels in conventional milk suggest the presence of synthetic growth hormone. Further research is needed to understand the impact of these differences, if any, on consumers.

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFβ1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFβ1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFβ1 alone, and TGFα relative to TGFβ1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.

Calcium and, to a lesser extent, dairy products are consistently modestly inversely associated with colorectal cancer (CRC). Dairy products may contain components other than calcium and fat, such as insulin-like growth factor-1, that may affect CRC risk. In the prospective Iowa Women’s Health Study, calcium, dairy product, and vitamin D intakes were assessed using a semiquantitative food frequency questionnaire. To investigate dairy products independent of their calcium components, we estimated residuals from linear regression models of their associations with dietary calcium. Of the 35,221 55–69-year-old cancer-free women at baseline in 1986, 1,731 developed CRC during follow-up through 2012. For those in the highest relative to the lowest intake quintiles, the adjusted hazards ratios and 95% confidence intervals from multivariable Cox proportional hazards regression models for overall and distal CRC were 0.81 (0.67–0.98; P(trend)=0.004) and 0.59 (0.44–0.80; P(trend)=0.003), respectively, for total calcium; and 0.79 (0.66–0.94; P(trend)=0.01) and 0.69 (0.53–0.90; P(trend)=0.003) for total dairy products, respectively. The various dairy product residuals were not associated with CRC. These results support that, among women, calcium and dairy products may be inversely associated with CRC—perhaps primarily distal CRC—but suggest that the non-calcium, non-fat component of dairy products may not be associated with CRC.

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).We examined the individual and joint associations between BMI (kg/mBMI 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/mOur 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.

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21–0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21–1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features., Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.

Background: Kidney cancer has several well-established risk factors, including smoking, obesity, and hypertension. These factors do not, however, completely account for its etiology. One previous study of vitamin D–binding protein (DBP) and risk of renal cell carcinoma found a striking inverse association that warranted replication. Methods: We conducted a nested case–control study in the American Cancer Society Cancer Prevention Study-II Nutrition Cohort to prospectively examine circulating DBP concentration and renal cell carcinoma risk. Cases (n = 87) were matched 1:1 to controls on gender, race, age (±5 years), and date of blood collection (±30 days). ORs and 95% confidence intervals (CIs) were estimated for quartiles of DBP using conditional logistic regression. Results: There was a statistically significant inverse trend across quartiles of DBP such that participants with higher DBP had a markedly decreased risk of renal cell carcinoma (vs. Q1: Q2 OR, 0.93; 95% CI, 0.41–2.11; Q3 OR, 0.42; 95% CI, 0.15–1.15; Q4 OR, 0.33; 95% CI, 0.10–1.06; Ptrend = 0.03). Conclusions: Our findings demonstrate a strong inverse association between circulating DBP and risk of renal cell carcinoma, supporting the findings from previous research. Impact: This is only the second study to examine DBP and risk of kidney cancer, and one of only a handful of studies to examine circulating DBP and risk of cancer at any site. Our findings support emerging evidence for an etiologic role of DBP in cancer and may provide insights into the etiology of kidney and other cancers. Cancer Epidemiol Biomarkers Prev; 27(10); 1203–7. ©2018 AACR.

BACKGROUND: Although α- and γ-tocopherol are co-consumed antioxidants, circulating γ-tocopherol concentrations were paradoxically found to be inversely associated with total vitamin E intake and circulating α-tocopherol concentrations. There are limited data on this apparent paradox or on determinants of circulating γ-tocopherol concentrations. OBJECTIVE: To help clarify possible determinants of circulating γ-tocopherol concentrations, we investigated associations of circulating γ-tocopherol concentrations with various dietary and lifestyle factors and biomarkers of oxidative stress and inflammation. METHODS: We pooled cross-sectional data from 2 outpatient, adult, elective colonoscopy populations (pooled n = 419) on whom extensive dietary, lifestyle, and medical information was collected, and the following plasma concentrations were measured: α- and γ-tocopherol (via HPLC), F(2)-isoprostanes (FiPs; via gas chromatography–mass spectrometry), and high-sensitivity C-reactive protein (hsCRP; via latex-enhanced immunonephelometry). Multivariable general linear models were used to assess mean γ-tocopherol differences across quantiles of plasma antioxidant micronutrients, FiPs, and hsCRP; an oxidative balance score [OBS; a composite of anti- and pro-oxidant dietary and lifestyle exposures (a higher score indicates higher antioxidant relative to pro-oxidant exposures)]; and multiple dietary and lifestyle factors. RESULTS: Adjusted for serum total cholesterol, mean γ-tocopherol concentrations among those in the highest relative to the lowest tertiles of circulating α-tocopherol and β-carotene, the OBS, and total calcium and dietary fiber intakes were 31.0% (P

OBJECTIVES: The massive spread of the novel coronavirus SARS-CoV2 (COVID-19) and subsequent restrictive measures caused disruptions in daily routines and behaviors, including changes in diet that may have consequences on immediate health and longer term risk of chronic disease. Our objective was to assess two-year changes in diet quality among subgroups of the Cancer Prevention Study-3 (CPS-3) cohort. METHODS: In August 2020, an online COVID-19 survey that assessed food group intakes, meal sources, and COVID-related questions was completed by a subgroup of 2,335 CPS-3 participants. Paired t-tests evaluated reported change in behaviors from 2018 to 2020. A diet quality score assigned higher points for greater frequency of foods recommended by cancer prevention guidelines, and lower points for foods that are not recommended. RESULTS: While diet quality improved slightly, on average, from 2018 to 2020, consumption of component food groups decreased (P

Circulating insulin-like growth factor 1 (IGF-1) may be directly associated with colorectal cancer risk, and IGF binding protein 3 (IGFBP-3) is one of the most abundantly expressed binding proteins in various cancers. Calcium intakes, primarily from food, have been directly associated with circulating IGF-1, but whether supplemental calcium affects IGF-1 and IGFBP-3 is unknown. We tested the effects of 1.0 and 2.0 g of supplemental elemental calcium daily on circulating IGF-1 and IGFBP-3 concentrations in colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193). IGF-1 and IGFBP-3 were quantified using enzyme-linked immunoassay and quantitative Western ligand blot, respectively. We also assessed cross-sectional associations of these biomarkers with participants' baseline characteristics. We found no appreciable effect of calcium relative to placebo on circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio. Mean IGF-1 concentrations were 11.1% higher in those with greater milk intakes (P = 0.05). Mean IGF-1 and IGFBP-3 concentrations were, respectively, 18.0% (P = 0.003) and 16.5% (P = 0.01) higher in men and were monotonically lower with increasing age (both P = 0.01). IGFBP-3 was 17.7% higher among those with higher relative to no alcohol consumption (P = 0.04). While these results support previous findings that IGF-1 concentrations are higher with greater milk intakes, and IGF-1 and IGFBP-3 concentrations differ according to sex and age, they provide no evidence to suggest that supplemental calcium appreciably affects circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio in sporadic colorectal adenoma patients.

Calcium intake has been consistently, modestly inversely associated with colorectal neoplasms, and supplemental calcium reduced adenoma recurrence in clinical trials. Milk products are the major source of dietary calcium in the United States, but their associations with colorectal neoplasms are unclear. Data pooled from three colonoscopy-based case-control studies of incident, sporadic colorectal adenoma (n = 807 cases, 2,185 controls) were analyzed using multivariable unconditional logistic regression. Residuals from linear regression models of milk with dietary calcium were estimated as the noncalcium, insulin-like growth factor 1-containing component of milk. For total, dietary, and supplemental calcium intakes, the adjusted odds ratios (ORs) comparing the highest to the lowest intake quintiles were 0.94 (95% confidence interval [CI] 0.69-1.30), 0.86 (CI 0.62-1.20), and 0.99 (CI 0.77-1.27), respectively. The corresponding ORs for consumption of total milk products, total milk, nonfat milk, total milk product residuals, and nonfat milk residuals were, respectively, 0.99, 0.90, 0.92, 0.94, and 0.95; all CIs included 1.0. For those who consumed any whole milk relative to those who consumed none, the OR was 1.15 (CI 0.89-1.49). These results are consistent with previous findings of modest inverse associations of calcium intakes with colorectal adenoma, but suggest that milk products may not be associated with adenoma.

OBJECTIVES: Colonic microbiota can be modified by diet and other environmental exposures that are associated with risk of cancer and other diseases. In addition, the stool metabolome represents products formed by gut microbial utilization of foods, nutrients, and other compounds. The collection of stool samples for analyses of the microbiome and metabolome in prospective cohort studies may lead to a better understanding of diet and other factors in disease etiology. Most studies of the gut microbiome and metabolome have been small clinical studies and relied on the collection of stool samples that were quickly flash-frozen and stored with no preservative. However, this method of collection is not feasible in large epidemiologic studies in which participants would self-collect and ship samples to a central repository. Other methods may preclude metabolomic analyses or result in a limited amount of stool. METHODS: We designed a pilot study to inform stool collection procedures for participants enrolled in a nationwide prospective cohort study. In this pilot study, stool samples will be collected by 10 volunteers who will aliquot their sample into: 1) OMNIgene Gut collection kit, 2) 95% ethanol collection kit, (3) Fecal Occult Blood Test cards, and (4) a vial for fresh-frozen sample with no solution (i.e., the gold standard in this analysis). Fresh-frozen samples will be shipped overnight on dry ice to a central biorepository. The remaining samples will be: 1) shipped overnight on cold packs; 2) shipped overnight at ambient temperature; 3) shipped overnight after 4 days at ambient temperature; and 4) shipped overnight at ambient temperature, followed by 4-day incubation at 50 °C to mimic maximum shipment temperature. The reproducibility, stability, and accuracy of 16S sequencing and metabolomics in stool will be compared among the collection kits, and shipping and storage conditions. RESULTS: Initial results are anticipated by June 2019. CONCLUSIONS: The findings of this pilot study will inform future stool collection among Cancer Prevention Study-3 (CPS-3) participants, which, when analyzed with food frequency questionnaire data, will broaden our understanding of the role of diet in cancer risk. FUNDING SOURCES: The American Cancer Society funds the creation, maintenance, and updating of CPS-3.

Ca and dairy product intakes may be inversely associated with all-cause and cause-specific mortality, and non-Ca components of dairy products, such as insulin-like growth factor-1, may be independently associated with mortality. We investigated associations of Ca and dairy product intakes with all-cause, all-cancer, colorectal cancer (CRC) and CHD mortality among 35 221 55- to 69-year-old women in the prospective Iowa Women’s Health Study, who were cancer-free in 1986. We assessed diet using a Willett FFQ, and associations using multivariable Cox proportional hazards regression. We estimated residuals from linear regression models of dairy products with dietary Ca to investigate total and specific dairy products independent of their Ca content. Through 2012, 18 687 participants died, including 4665 from cancer (including 574 from CRC) and 3603 from CHD. For those in the highest relative to the lowest quintiles of intake, the multivariable-adjusted hazard ratios (HR) and 95 % CI for total Ca (dietary plus supplemental) were 0·88 (0·83, 0·93; P trend=0·001) for all-cause mortality, 0·91 (0·81, 1·02; P trend=0·34) for all-cancer mortality, 0·60 (0·43, 0·83; P trend=0·002) for CRC mortality and 0·73 (0·64, 0·83; P trend

Evidence supports a role of whole grains in colorectal cancer (CRC) prevention, but the association between gluten intake and CRC risk in healthy populations is unclear. We examined the association of grain and gluten intake with risk of CRC overall and by subsite among Cancer Prevention Study-II Nutrition Cohort participants. In 1999, 50,118 men and 62,031 women completed food frequency questionnaires assessing grain intake. Gluten intake was estimated using the protein content of grain products. Multivariable-adjusted hazards ratio (HR) and 95% confidence interval (CI) of CRC risk were estimated using Cox proportional hazards regression. During follow-up through 2013, 1742 verified CRC cases occurred. For the highest vs. lowest quintiles of whole grain intake, HRs (95% CIs) of CRC risk were 0.77 (0.61–0.97; P trend = 0.03) among men and 1.10 (95% CI 0.88–1.36; P trend = 0.14) among women (P interaction by sex = 0.01). Men in the highest vs. lowest quintile of whole grain intake had a 43% lower risk of rectal cancer (HR = 0.57, 95% CI 0.35–0.93, P trend = 0.04). Gluten intake was not associated with CRC risk overall (HR = 1.10, 95% CI 0.93–1.32, P trend = 0.10), but was associated with risk of proximal colon cancer among men and women, combined (HR = 1.37, 95% CI 1.07–1.75, quintile 5 vs. 1, P trend = 0.001) and separately. Refined grains and grain-based sweets were not associated with CRC risk. We found that higher whole grain intake was associated with lower CRC risk among older US men, but not women. The positive association of gluten intake with the risk of proximal colon cancer deserves further study.

Various individual diet and lifestyle factors are associated with mortality. Investigating these factors collectively may help clarify whether dietary and lifestyle patterns contribute to life expectancy. We investigated the association of previously described evolutionary-concordance and Mediterranean diet pattern scores and a novel evolutionary-concordance lifestyle pattern score with all-cause and cause-specific mortality in the prospective Iowa Women’s Health Study (1986–2012). We created the diet pattern scores from Willett FFQ responses, and the lifestyle pattern score from self-reported physical activity, BMI and smoking status, and assessed their associations with mortality, using multivariable Cox proportional hazards regression. Of the 35 221 55- to 69-year-old cancer-free women at baseline, 18 687 died during follow-up. The adjusted hazard ratios (HR) and 95 % CI for all-cause, all CVD, and all-cancer mortality among participants in the highest relative to the lowest quintile of the evolutionary-concordance lifestyle score were, respectively, 0·52 (95 % CI 0·50, 0·55), 0·53 (95 % CI 0·49, 0·57) and 0·51 (95 % CI 0·46, 0·57). The corresponding findings for the Mediterranean diet score were HR 0·85 (95 % CI 0·82, 0·90), 0·83 (95 % CI 0·76, 0·90) and 0·93 (95 % CI 0·84, 1·03), and for the evolutionary-concordance diet score they were close to null and not statistically significant. The lowest estimated risk was among those in the highest joint quintile of the lifestyle score and either diet score (both Pinteraction

Background The association between coffee consumption and colorectal cancer risk generally appears null, but recent evidence suggests that risk may vary by coffee type. We examined associations of caffeinated and decaffeinated coffee intake with colorectal cancer risk overall and with colon and rectum separately, among older U.S. men and women. Methods In 1999, 47,010 men and 60,051 women with no previous diagnosis of cancer, aged 47–96 years, in the Cancer Prevention Study-II Nutrition Cohort completed a food frequency questionnaire that assessed caffeinated and decaffeinated coffee intake; consumption was updated in 2003. A total of 1829 colorectal cancer cases were verified through June 2015. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusting for smoking history, alcohol, caffeinated/decaffeinated coffee intake (depending on the model), and other colorectal cancer risk factors. Results Consumption of ≥2 cups/day of decaffeinated coffee, compared to no decaffeinated coffee, was associated with lower risk of overall colorectal cancer (HR = 0.82, 95% CI: 0.69−0.96, P-trend = 0.04), colon cancer (HR = 0.82, 95% CI: 0.69−0.99, P-trend = 0.05) and rectal cancer (HR = 0.63, 95% CI: 0.40−0.99, P-trend = 0.17). Consumption of ≥2 cups/day of caffeinated coffee was associated with higher risk of rectal cancer (HR = 1.37, 95% CI: 0.99–1.89, P-trend = 0.04), but not with colorectal or colon cancer. Conclusion In this prospective study, higher intake of decaffeinated coffee was associated with lower risk of colorectal, colon, and rectal cancers. Further study on associations of caffeinated and decaffeinated coffee with colorectal cancer risk by subsite is needed.

OBJECTIVES: Emulsifiers may increase intestinal permeability, inflammation, and colorectal carcinogenesis in animals. Highly processed foods are associated with obesity and may increase risk of chronic diseases, including cancer. We estimated intake of emulsifiers and highly processed foods in participants from the Cancer Prevention Study-3 Diet Assessment Sub-study and examined their association with biomarkers of gut permeability and inflammation. METHODS: This study included 657 men and women who completed six 24-hr dietary recalls and two fasting blood samples over one year. Antibodies (IgG and IgA) to flagellin and lipopolysaccharide (LPS) and glycoprotein acetyls (GlycA) were measured using enzyme-linked immunosorbent assay and nuclear magnetic resonance, respectively. Total flagellin and LPS were each calculated as the sum of IgG and IgA; total antibody comprised the sum of total flagellin and LPS. Foods containing ≥1 emulsifier were identified from ingredient lists; foods typically containing emulsifiers were coded as such if an ingredient list was not available. We estimated emulsifier intake as 0.5% of total food weight, per FDA guidance. Highly processed foods were defined using the NOVA and Poti et al. classification systems and calculated as % grams of total foods and % kcal of total energy. Multivariable-adjusted generalized linear models were used to estimate associations of emulsifier and processed food quartiles with continuous antibody or inflammatory biomarkers. RESULTS: Higher emulsifier intake (g/d) was not associated with total flagellin (P-trend = 0.48), total LPS (P-trend = 0.61), total antibody (P-trend = 0.49), or GlycA (P-trend = 0.16). Higher processed food intake (% kcal/d) was associated with higher total LPS (P-trend = 0.001) and total antibody (P-trend = 0.01) but not with other biomarkers, whereas processed food intake estimated as % g/d was only associated with higher GlycA (P-trend = 0.02). CONCLUSIONS: Our results suggest highly processed food, but not emulsifier, intake may be associated with gut permeability biomarkers. Additional studies are needed to further understand the relationship between emulsifier and highly processed food intake and intestinal permeability and inflammation. FUNDING SOURCES: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-3 cohort.

Whole grains are recommended as part of a healthy dietary pattern for the prevention of chronic diseases, including colorectal cancer. Greater whole grain consumption may beneficially alter gut microbiota, and it is unclear if gluten, a protein component of grains, is also associated with altered microbiota. To examine the association between grain, gluten, and fiber intake with gut microbiota, we analyzed data from the ongoing prospective Food and Microbiome Longitudinal Investigation Study. This cross-sectional analysis included 300 men and 501 women of White, Black, Hispanic, and Asian race/ethnicity who completed a 137-item semiquantitative food frequency questionnaire. Gluten intake was estimated using the protein content of grain products. Bacterial 16S rRNA genes from stool samples collected via RNAlater tubes were amplified, sequenced, and assigned to bacterial taxa. We examined associations of whole and refined grain, gluten, and dietary fiber intakes with gut microbiota diversity and composition using multivariable-adjusted linear regression models and permutational multivariate analysis of variance, respectively, and with microbial taxa abundance using analysis of composition of microbiomes (ANCOM). In this diverse study population, the highest quartiles of energy-adjusted refined grain and gluten intake, when compared to the lowest quartiles, were associated with lower Shannon diversity (P-trend=0.03 and P-trend=0.01, respectively), but no other associations with alpha- or beta-diversity measures were observed. The highest quartile of dietary fiber was not associated with alpha-diversity measures but was associated with shifts in overall gut microbial composition (P-trend=0.02). Whole grain intake was not statistically significantly associated with these microbiome parameters. However, the highest quartile of whole grain intake, compared to the lowest quartile, was associated with greater abundance of several gut taxa, including classes Erysipelotrichi (family Erysipelotrichaceae), Clostridia (genus Faecalibacterium and Lachnospira), and Bacteroidia (Bacteroides plebeius). Higher whole grain intake was also associated with lower abundance of classes Bacteroidia (family Rikenellaceae and Bacteroides uniformis) and Clostridia (genus Oscillospira and Ruminococcus). Similarly, the highest quartile of dietary fiber intake was associated with greater abundance of classes Erysipelotrichi (family Erysipelotrichaceae) and Clostridia (genus Lachnospira) and lower abundance of class Bacteroidia (family Rikenellaceae). Higher intakes of refined grain and gluten were not statistically significantly associated with altered abundance of gut taxa. Though this study is cross-sectional, identification of gut microbes associated with higher intakes of whole grain and fiber may expand our understanding of how these nutritional factors lower risk for colorectal cancer. Citation Format: Caroline Y. Um, Brandilyn A. Peters, Emilia N. Cobbs, Hee Sun Choi, Dia B. Beggs, Richard B. Hayes, Marjorie L. McCullough, Susan M. Gapstur, Jiyoung Ahn. Cross-sectional analysis of grain, gluten, and fiber intakes and gut microbiota in the Food and Microbiome Longitudinal Investigation (FAMiLI) Study [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B12.

Background: Despite considerable biological plausibility, other than for calcium, there are few reported epidemiologic studies on mineral intake–colorectal cancer associations, none of which investigated multiple minerals in aggregate. Methods: Accordingly, we incorporated 11 minerals into a mineral score and investigated its association with incident colorectal cancer in the Iowa Women's Health Study, a prospective cohort study of 55- to 69-year-old women who completed a food frequency questionnaire in 1986. In the analytic cohort (n = 35, 221), 1,731 incident colorectal cancer cases were identified via the State Health Registry of Iowa. Participants' calcium, magnesium, manganese, zinc, selenium, potassium, and iodine intakes were ranked 1 to 5, with higher ranks indicating higher, potentially anticarcinogenic, intakes, whereas for iron, copper, phosphorus, and sodium intakes, the rankings were reversed to account for their possible procarcinogenic properties. The rankings were summed to create each woman's mineral score. The mineral score–incident colorectal cancer association was estimated using multivariable Cox proportional hazards regression. Results: There was decreasing risk with an increasing score (Ptrend = 0.001). The hazard ratios and 95% confidence intervals (CI) for those in mineral score quintiles 2 to 5 relative to those in the lowest were 0.91 (CI, 0.88–1.08), 0.85 (CI, 0.75–0.95), 0.86 (CI, 0.75–0.97), and 0.75 (CI, 0.71–0.95), respectively. Conclusions: Our findings suggest that a predominance of putative anti- relative to pro-colorectal carcinogenic mineral intakes may be inversely associated with colorectal cancer risk. Impact: These results support further investigation of colorectal cancer etiology using composite mineral intake scores.

Background & Aims Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. Methods We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. Results Overall, 40% of controls and 41% of cases were H pylori–seropositive (odds ratio [OR], 1.09; 95% CI, 0.99–1.20). H pylori VacA–specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01–1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08–1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). Conclusions In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

Background: Acrylamide, an industrial chemical and probable human carcinogen, can be formed in primarily carbohydrate-containing foods during high-heat cooking or processing. Most epidemiologic studies show no associations of dietary acrylamide intake with most cancer outcomes, but limited prospective evidence suggests a positive association with renal cell carcinoma (RCC). Methods: In 1999, 102,154 men and women from the Cancer Prevention Study-II Nutrition Cohort completed a questionnaire on diet, lifestyle, and cancer risk factors and were followed through June 30, 2013. Cox proportional hazards regression was used to estimate the HR and 95% confidence interval (CI) for the association between estimated dietary acrylamide intake and risk of RCC. Results: After 1,137,441 person-years of follow-up, 412 cases of invasive RCC occurred. In multivariable-adjusted models, there was no association between acrylamide intake and risk of RCC (HR = 1.09; 95% CI, 0.82–1.43) for the highest versus lowest quartile of intake. Associations were not modified by sex or smoking history. Conclusions: We found no associations between dietary acrylamide exposure and risk of invasive RCC. Impact: The findings from this large, prospective analysis do not support a positive association between higher dietary acrylamide intake and RCC risk.

Background: Dietary guidelines recommend consumption of 1% or skim (i.e. non-fat) milk for children >2 years due to concerns about the role of saturated fat in raising low-density lipoprotein cholesterol (LDL) levels and cardiovascular disease risk. Low- or non-fat milk is also recommended to promote energy balance and reduce obesity risk. While more recent evidence in adults suggests no association between milkfat and cardiovascular disease risk, this association has not been well studied among children who tend to be the highest consumers of milk. No known studies have demonstrated an association between milkfat consumption and lipid levels in children. Our objective was to determine if there is an association between milk fat consumption and risk of dyslipidemia and obesity among U.S. children. Methods: We used cross-sectional data from children 2-19 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 (n=7261). Usual milkfat intake (i.e. never/rare milk consumption, non-fat, 1%, 2%, or whole) was self-reported by parent or child. Lipid levels (12-19 years only) and adiposity (BMI z-score and weight category [underweight, normal, overweight, or obese] in all ages) were assessed by trained staff using standardized methods. Covariates included child age, sex, household income, race/ethnicity, physical activity, dieting, and total energy intake. We used multivariate linear and logistic regression models to examine the association between milkfat consumption and our outcomes and conducted pairwise comparisons to assess differences between different milkfat consumers. Results: Most children consumed 2% milk (42.3%), followed by whole (26.1%), 1% milk (11.7%), never/rare consumption (10.2%), and nonfat (9.7%). We found no significant trends in mean cholesterol (total, HDL, LDL) with consumption of milk with greater fat content. There was a significant trend towards higher triglycerides as milkfat intake increased (p=0.01) though this association was stronger among 2% milk compared to whole fat consumers. We found no significant trend in prevalence of each BMI category across milk fat intake. Pairwise comparisons demonstrated that usual consumption of 1% and 2% milkfat was associated with both higher BMI Z-score and odds of obesity compared to whole milk. Conclusion: We found no significant linear trend between usual %milk fat consumed and indicators of cardiovascular disease (BMI-Z and lipid levels) in children, except for triglycerides which rose as milkfat intake increased. However, triglycerides were higher among the 2% compared to whole milkfat consumers. Overall, whole milk was not associated with increased indicators of cardiovascular disease risk in children.

Background: The oral microbiota play a central role in oral health, and possibly in carcinogenesis. Research suggests that coffee and tea consumption may have beneficial health effects. We examined the associations of these common beverages with the oral ecosystem in a large cross-sectional study. Methods: We assessed oral microbiota in mouthwash samples from 938 participants in two U.S. cohorts using 16S rRNA gene sequencing. Coffee and tea intake were assessed from food frequency questionnaires. We examined associations of coffee and tea intake with overall oral microbiota diversity and composition using linear regression and permutational MANOVA, respectively, and with taxon abundance using negative binomial generalized linear models; all models adjusted for age, sex, cohort, body mass index, smoking, ethanol intake, and energy intake. Results: Higher tea intake was associated with greater oral microbiota richness (P = 0.05) and diversity (P = 0.006), and shifts in overall community composition (P = 0.002); coffee was not associated with these microbiome parameters. Tea intake was associated with altered abundance of several oral taxa; these included Fusobacteriales, Clostridiales, and Shuttleworthia satelles (higher with increasing tea) and Bifidobacteriaceae, Bergeyella, Lactobacillales, and Kingella oralis (lower with increasing tea). Higher coffee intake was only associated with greater abundance of Granulicatella and Synergistetes. Conclusions: In the largest study to date of tea and coffee consumption in relation to the oral microbiota, the microbiota of tea drinkers differed in several ways from nondrinkers. Impact: Tea-driven changes to the oral microbiome may contribute to previously observed associations between tea and oral and systemic diseases, including cancers. Cancer Epidemiol Biomarkers Prev; 27(7); 814–21. ©2018 AACR.