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Tea is frequently consumed worldwide, but the association of tea drinking with mortality risk remains inconclusive in populations where black tea is the main type consumed.To evaluate the associations of tea consumption with all-cause and cause-specific mortality and potential effect modification by genetic variation in caffeine metabolism.Prospective cohort study.The UK Biobank.498 043 men and women aged 40 to 69 years who completed the baseline touchscreen questionnaire from 2006 to 2010.Self-reported tea intake and mortality from all causes and leading causes of death, including cancer, all cardiovascular disease (CVD), ischemic heart disease, stroke, and respiratory disease.During a median follow-up of 11.2 years, higher tea intake was modestly associated with lower all-cause mortality risk among those who drank 2 or more cups per day. Relative to no tea drinking, the hazard ratios (95% CIs) for participants drinking 1 or fewer, 2 to 3, 4 to 5, 6 to 7, 8 to 9, and 10 or more cups per day were 0.95 (95% CI, 0.91 to 1.00), 0.87 (CI, 0.84 to 0.91), 0.88 (CI, 0.84 to 0.91), 0.88 (CI, 0.84 to 0.92), 0.91 (CI, 0.86 to 0.97), and 0.89 (CI, 0.84 to 0.95), respectively. Inverse associations were seen for mortality from all CVD, ischemic heart disease, and stroke. Findings were similar regardless of whether participants also drank coffee or not or of genetic score for caffeine metabolism.Potentially important aspects of tea intake (for example, portion size and tea strength) were not assessed.Higher tea intake was associated with lower mortality risk among those drinking 2 or more cups per day, regardless of genetic variation in caffeine metabolism. These findings suggest that tea, even at higher levels of intake, can be part of a healthy diet.National Cancer Institute Intramural Research Program.

Background: Coffee drinking has been inversely associated with mortality as well as cancers of the endometrium, colon, skin, prostate, and liver. Improved insulin sensitivity and reduced inflammation are among the hypothesized mechanisms by which coffee drinking may affect cancer risk; however, associations between coffee drinking and systemic levels of immune and inflammatory markers have not been well characterized.Methods: We used Luminex bead-based assays to measure serum levels of 77 immune and inflammatory markers in 1,728 older non-Hispanic Whites. Usual coffee intake was self-reported using a food frequency questionnaire. We used weighted multivariable logistic regression models to examine associations between coffee and dichotomized marker levels. We conducted statistical trend tests by modeling the median value of each coffee category and applied a 20% false discovery rate criterion to P values.Results: Ten of the 77 markers were nominally associated (P trend < 0.05) with coffee drinking. Five markers withstood correction for multiple comparisons and included aspects of the host response namely chemotaxis of monocytes/macrophages (IFNγ, CX3CL1/fractalkine, CCL4/MIP-1β), proinflammatory cytokines (sTNFRII), and regulators of cell growth (FGF-2). Heavy coffee drinkers had lower circulating levels of IFNγ [odds ratios (OR), 0.35; 95% confidence intervals (CI), 0.16–0.75], CX3CL1/fractalkine (OR, 0.25; 95% CI, 0.10–0.64), CCL4/MIP-1β (OR, 0.48; 95% CI, 0.24–0.99), FGF-2 (OR, 0.62; 95% CI, 0.28–1.38), and sTNFRII (OR, 0.34; 95% CI, 0.15–0.79) than non-coffee drinkers.Conclusions: Lower circulating levels of inflammatory markers among coffee drinkers may partially mediate previously observed associations of coffee with cancer and other chronic diseases.Impact: Validation studies, ideally controlled feeding trials, are needed to confirm these associations. Cancer Epidemiol Biomarkers Prev; 24(7); 1052–60. ©2015 AACR.

Supplementary Figure 1 from Comparison of Collection Methods for Fecal Samples for Discovery Metabolomics in Epidemiologic Studies

SupplementaryTable S5. Odds ratios (OR) for high versus low levels e for eight circulating inflammatory markers (P-trend

Supplementary Table S4. Categorization of markers by weighted percent of values below the lower limit of detection (LOD)

Background: The gut metabolome may be associated with the incidence and progression of numerous diseases. The composition of the gut metabolome can be captured by measuring metabolite levels in the feces. However, there are little data describing the effect of fecal sample collection methods on metabolomic measures.Methods: We collected fecal samples from 18 volunteers using four methods: no solution, 95% ethanol, fecal occult blood test (FOBT) cards, and fecal immunochemical test (FIT). One set of samples was frozen after collection (day 0), and for 95% ethanol, FOBT, and FIT, a second set was frozen after 96 hours at room temperature. We evaluated (i) technical reproducibility within sample replicates, (ii) stability after 96 hours at room temperature for 95% ethanol, FOBT, and FIT, and (iii) concordance of metabolite measures with the putative “gold standard,” day 0 samples without solution.Results: Intraclass correlation coefficients (ICC) estimating technical reproducibility were high for replicate samples for each collection method. ICCs estimating stability at room temperature were high for 95% ethanol and FOBT (median ICC > 0.87) but not FIT (median ICC = 0.52). Similarly, Spearman correlation coefficients (rs) estimating metabolite concordance with the “gold standard” were higher for 95% ethanol (median rs = 0.82) and FOBT (median rs = 0.70) than for FIT (median rs = 0.40).Conclusions: Metabolomic measurements appear reproducible and stable in fecal samples collected with 95% ethanol or FOBT. Concordance with the “gold standard” is highest with 95% ethanol and acceptable with FOBT.Impact: Future epidemiologic studies should collect feces using 95% ethanol or FOBT if interested in studying fecal metabolomics. Cancer Epidemiol Biomarkers Prev; 25(11); 1483–90. ©2016 AACR.

Metabolites in fecal samples collected with no solution that were frozen immediately (day 0) by super and sub metabolic pathway

Background: Regular aspirin use may decrease cancer risk by reducing chronic inflammation. However, associations between aspirin use and circulating markers of inflammation have not been well studied.Methods: Serum levels of 78 inflammatory markers were measured in 1,819 55- to 74-year-old men and women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Data were combined from three completed case–control studies and reweighted to the PLCO screening arm. Self-reported aspirin and ibuprofen use (number of tablets taken per day/week/month) over the previous 12 months was collected at baseline. Associations between (i) nonregular (Results: Aspirin use was nominally associated with (Ptrend across categories ≤ 0.05) decreased levels of chemokine C-C motif ligand 15 [CCL15; OR, 0.5; 95% confidence intervals (CI), 0.3–0.8; moderate versus nonregular use]; soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 0.7; 95% CI, 0.4–1.0); soluble tumor necrosis factor receptor 1 (sTNFR1; OR, 0.6; 95% CI, 0.4–0.9) and increased levels of CCL13 (OR, 1.3; 95% CI, 0.8–2.1); CCL17 (OR, 1.1; 95% CI, 0.7–1.9) and interleukin 4 (IL4; OR, 1.6; 95% CI, 0.9–2.8). Trends were not statistically significant following correction for multiple comparisons. Likewise, no statistically significant associations were observed between ibuprofen use and marker levels.Conclusions: No significant associations were observed between regular aspirin use and the inflammatory markers assessed.Impact: Additional studies are needed to better understand the relationship between aspirin use, chronic inflammation, and cancer risk. Cancer Epidemiol Biomarkers Prev; 24(5); 825–32. ©2015 AACR.

Metabolites in fecal samples collected with FIT tubes that were frozen immediately (day 0) by super and sub metabolic pathway

Number of metabolites in fecal samples by collection method and time

Supplemental Tables 1-7 and Methods. Details on development of sampling weights and their use in analysis. Supplemental Table 1. Description of three case-control studies nested within PLCO. Supplemental Table 2. Multiplex immune panel markers measured in the PLCO Cancer Screening Study. Supplemental Table 3: Percent detection and median levels for each inflammatory marker by original study. Supplemental Table 4: Participant characteristics for i) the 1,819 individuals with inflammatory marker data, ii) the weighted population and iii) those in the PLCO screening arm that met the study eligibility criteria. Supplemental Table 5: Associations between regular aspirin use and circulating inflammatory markers2, restricted to individuals without a history of chronic heart disease, stroke or arthritis. Supplemental Table 6: Associations between regular aspirin use and circulating inflammatory markers2, by study. Supplemental Table 7: Associations between regular aspirin use and circulating inflammatory markers.

Technical reproducibility, stability, and concordance for metabolites with {greater than or equal to}80% detectability in samples with no solution and in samples collected with ethanol, FOBT, or FIT

Metabolites in fecal samples collected with FOBT cards that were frozen immediately (day 0) by super and sub metabolic pathway

Participant characteristics (N=18)

BACKGROUND: A growing body of literature suggests chronically higher bile acid (BA) concentrations may be associated with multiple health conditions. Diet may affect BA metabolism and signaling; however, evidence from human populations is lacking. OBJECTIVES: We systematically investigated cross-sectional associations of a priori–selected dietary components (fiber, alcohol, coffee, fat) with circulating BA concentrations. METHODS: We used targeted, quantitative LC-MS/MS panels to measure 15 circulating BAs in a subset of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC; n = 2224) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; n = 986) comprising Finnish male smokers and United States men and women, respectively. We used multivariable linear regression to estimate associations of each dietary component with log-transformed BAs; exponentiated coefficients estimate proportional differences. We included the median of the dietary component quartile in linear regression models to test for trend. RESULTS: In ATBC, fiber was inversely associated with multiple circulating BAs. The proportional difference was –10.09% (95% CI: −19.29 to 0.16; P-trend = 0.04) when comparing total BAs among those in the highest relative to the lowest fiber quartile. Alcohol, trans fat, and polyunsaturated fat were positively associated with BAs in ATBC. The proportional difference comparing total BAs among those in the highest relative to the lowest alcohol quartile was 8.76% (95% CI: –3.10 to 22.06; P-trend = 0.03). Coffee and monounsaturated fat were inversely associated with BAs. The proportional difference comparing total BAs among those in the highest relative to the lowest coffee quartile was –24.03% (95% CI: –31.57 to –15.66; P-trend

Background Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations. Methods We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model. Results In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption. Conclusions In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.

PURPOSE Higher levels of sedentary behavior are associated with early mortality, but the distribution of sedentary time by classes of behavior and demographic groups is poorly described in U.S. adults. To quantify the amount and sources of sedentary time in U.S. adults, we conducted a nationwide survey using a novel validated self-administered previous-day recall method and compared these values with a commonly used sitting time question. METHODS Participants from the AmeriSpeak panel 20 to 75 yr of age (N = 2640) completed up to two activities completed over time in 24 h (ACT24) previous-day recalls. Recalls were conducted on randomly selected days in October and November 2019. Survey sample designs were applied to reflect the U.S. population. RESULTS Mean age was 45.3 yr, 51% were female, 67% non-Hispanic White, and 37% had a body mass index of ≥30 kg·m-2. U.S. adults reported a mean 9.5 h·d-1 of sedentary time (95% confidence interval = 9.4, 9.7 h·d-1), which was 34% more than reported using a common surveillance measure (P < 0.01). Most daily sedentary time was accumulated in the leisure and work life domains, with leisure accounting for 47% (4.3 h·d-1, 95% confidence interval = 4.2, 4.5 h·d-1) of the total sedentary time. Eighty-two percent of leisure time was spent sedentary, mainly watching television/videos or engaged in Internet/computer use. CONCLUSIONS U.S. adults appear to spend more time in sedentary behavior than previously thought, and the majority of this time is accumulated at work and in leisure time. Reducing sedentary screen time during leisure in favor of physically active could be an important intervention target in the effort to increase physical activity in U.S. adults.

Aims/hypothesis The gut microbiome is hypothesised to be related to insulin resistance and other metabolic variables. However, data from population-based studies are limited. We investigated associations between serologic measures of metabolic health and the gut microbiome in the Northern Finland Birth Cohort 1966 (NFBC1966) and the TwinsUK cohort. Methods Among 506 individuals from the NFBC1966 with available faecal microbiome (16S rRNA gene sequence) data, we estimated associations between gut microbiome diversity metrics and serologic levels of HOMA for insulin resistance (HOMA-IR), HbA1c and C-reactive protein (CRP) using multivariable linear regression models adjusted for sex, smoking status and BMI. Associations between gut microbiome diversity measures and HOMA-IR and CRP were replicated in 1140 adult participants from TwinsUK, with available faecal microbiome (16S rRNA gene sequence) data. For both cohorts, we used general linear models with a quasi-Poisson distribution and Microbiome Regression-based Kernel Association Test (MiRKAT) to estimate associations of metabolic variables with alpha- and beta diversity metrics, respectively, and generalised additive models for location scale and shape (GAMLSS) fitted with the zero-inflated beta distribution to identify taxa associated with the metabolic markers. Results In NFBC1966, alpha diversity was lower in individuals with higher HOMA-IR with a mean of 74.4 (95% CI 70.7, 78.3) amplicon sequence variants (ASVs) for the first quartile of HOMA-IR and 66.6 (95% CI 62.9, 70.4) for the fourth quartile of HOMA-IR. Alpha diversity was also lower with higher HbA1c (number of ASVs and Shannon’s diversity, p p = 0.003, respectively) and higher CRP (number of ASVs, p = 0.025), even after adjustment for BMI and other potential confounders. In TwinsUK, alpha diversity measures were also lower among participants with higher measures of HOMA-IR and CRP. When considering beta diversity measures, we found that microbial community profiles were associated with HOMA-IR in NFBC1966 and TwinsUK, using multivariate MiRKAT models, with binomial deviance dissimilarity p values of Prevotella and Blautia were associated with HOMA-IR in both cohorts. Conclusions/interpretation Overall, higher levels of HOMA-IR, CRP and HbA1c were associated with lower microbiome diversity in both the NFBC1966 and TwinsUK cohorts, even after adjustment for BMI and other variables. These results from two distinct population-based cohorts provide evidence for an association between metabolic variables and gut microbial diversity. Further experimental and mechanistic insights are now needed to provide understanding of the potential causal mechanisms that may link the gut microbiota with metabolic health. Graphical abstract

INTRODUCTION: Diet may affect bile acid (BA) metabolism and signaling. In turn, BA concentrations may be associated with cancer risk. We investigated (i) associations of BA concentrations with adenoma recurrence and (ii) the effect of a high-fiber, high-fruit and vegetable, and low-fat dietary intervention on serum BA concentrations. METHODS: The Polyp Prevention Trial is a 4-year randomized, controlled trial that investigated the effect of a high-fiber, high-fruit and vegetable, and low-fat diet on colorectal adenoma recurrence. Among 170 participants who reported adhering to the intervention and 198 comparable control arm participants, we measured 15 BAs in baseline, year 2, and year 3 serum using targeted, quantitative liquid chromatography-tandem mass spectrometry. We estimated associations of BAs with adenoma recurrence using multivariable logistic regression and the effect of the dietary intervention on BA concentrations using repeated-measures linear mixed-effects models. In a subset (N = 65), we investigated associations of BAs with 16S rRNA gene sequenced rectal tissue microbiome characteristics. RESULTS: Baseline total BA concentrations were positively associated with adenoma recurrence (odds ratio Q3 vs Q1 = 2.17; 95% confidence interval = 1.19-4.04; Ptrend = 0.03). Although we found no effect of the dietary intervention on BA concentrations, pretrial dietary fiber intake was inversely associated with total baseline BAs (Spearman = -0.15; PFDR = 0.02). BA concentrations were associated with potential colorectal neoplasm-related microbiome features (lower alpha diversity and higher Bacteroides abundance). DISCUSSION: Baseline circulating BAs were positively associated with adenoma recurrence. Although the dietary intervention did not modify BA concentrations, long-term fiber intake may be associated with lower concentrations of BAs that are associated with higher risk of adenoma recurrence.

Introduction Shift work leading to circadian disruption is associated with increased breast cancer risk, but it remains unclear whether typical sleep timing variation in the general population that may cause less extreme disruption is also associated with increased risk. Prior studies relied on sleep timing assessed using self-report, but research using actigraphy is limited. Our goal was to characterize the association between sleep timing and breast cancer risk using actigraphy-based measures. Methods Our sample included 43,109 women without a history of breast cancer in the UK Biobank cohort who wore Axivity-AX3 accelerometers over 7 days. We estimated sleep midpoints, the median of sleep onset and waking. Social jetlag was estimated as the absolute difference in average weekend and weekday sleep midpoints. We used multivariable Cox models to estimate hazards ratios (HRs) and 95% confidence intervals (CI), adjusting for age, body mass index, participant characteristics, socioeconomic status, physical activity, menopause, parity, and oral contraceptive use. We conducted a sensitivity analysis excluding shift workers to control for potential strong confounding from shift work. Results Over 6.2 years of follow-up, there were 683 incident breast cancer cases. Earlier and later sleep midpoints were not associated with breast cancer (Early, < 4:00AM HR:1.08 [95%CI: 0.89-1.32]; Later, ≥5:00AM HR:1.24 [0.86-1.81]; vs. Reference 4:00-4:59 AM). Per-hour increases in social jetlag were suggestively associated with greater breast cancer risk (HR:1.09 [0.96-1.24]), but significantly higher risk was only noted at the highest levels of social jetlag comparing ≥2 hours to < 1 hour (HR:1.58 [1.13-2.20]). Results were unchanged when excluding shift workers. Conclusion Higher levels of social jetlag among UK women appeared to be associated with elevated breast cancer risk, possibly due to circadian disruption. While our results suggest that minimizing variation between weekday and weekend sleep timing may be related to lower breast cancer risk, replication of our findings in future studies using actigraphy-based measures and larger case numbers is needed. Support (if any) Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

Background: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent synthetic chemicals detectable in the blood of most Americans. Elevated exposures to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), the two most prevalent PFAS, have been associated with several health outcomes including metabolic outcomes and some cancers. To evaluate possible mechanisms related to the biological effects of these chemicals, we conducted a pooled metabolome-wide association study (MWAS) of circulating PFOS and PFOA among 3,647 participants included in one of eight nested case-control serum metabolomic profiling studies conducted in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) population. Methods: All metabolomic profiling was conducted by Metabolon Inc, using liquid-phase or gas chromatography coupled with mass spectrometry. All metabolites including PFOS and PFOA were centered (mean=0, standard deviation=1) and log-transformed. We conducted multivariable linear regression analyses to estimate study-specific associations between metabolite levels and PFOS and PFOA, adjusted for age at specimen collection, race/ethnicity, body mass index, smoking, case-control status, study center, and year of specimen collection. Sex was additionally adjusted for studies including both men and women. We then conducted combined the study-specific findings through meta-analysis using random effects models. Results: The meta-analysis results of 1,040 metabolites for PFOS and 1,103 for PFOA identified 83 and 67 metabolites, respectively, associated at Bonferroni-corrected significance thresholds (P=4.81 × 10−5 for PFOS; P=4.53 × 10−5 for PFOA). For both PFOS and PFOA, the strongest positive associations were observed for the xenobiotics 3,5-dichloro-2,6-dihydroxybenzoic acid [PFOS, summary beta coefficient =0.74, 95% confidence interval=0.67,0.80; PFOA, 0.48 (0.35,0.61)] and 3-bromo-5-chloro-2,6-dihydroxybenzoic acid [0.57 (0.43,0.72) and 0.39 (0.23,0.55)]. We also observed strong positive associations with PFOS and PFOA for metabolites related to the sphingomyelin (SM) pathway, such as hydroxypalmitoyl sphingomyelin (d18:1/16:0(OH)) [PFOS, 0.44 (0.24,0.64)] and SM (d18:1/18:0) [PFOS, 0.35 (0.24,0.46); PFOA, 0.25 (0.16,0.34)], and SM (d18:2/24:2) [PFOS, 0.32 (0.17,0.47)]. The PFOS metabolite associations remained after model adjustment for PFOA; however, the PFOA associations were greatly attenuated after controlling for PFOS. Conclusions: In this MWAS of PFAS, to our knowledge the largest to date, we observed robust positive associations with serum PFOS for several xenobiotic compounds and for metabolites related to the sphingomyelin pathway. Further investigation of these metabolites may offer insight into PFOS-related biologic effects contributing to disease development. Citation Format: Jongeun Rhee, Steven C. Moore, Demetrius Albanes, Tracy M. Layne, Erikka Loftfield, Rachael Stolzenberg-Solomon, Linda M. Liao, Mary C. Playdon, Mark P. Purdue. A metabolomic investigation of serum perfluorooctane sulfonate and perfluorooctanoate. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4223.

Background: The gut microbiome (GM) and the metabolites it produces and regulates, such as bile acids (BAs), may act individually or interact to influence colorectal cancer development. We used data from a multi-center screening study to investigate the associations of the normal colon tissue microbiome and circulating BAs with colorectal adenoma. Methods: We used data from the multi-center Colorectal Neoplasia Screening with Colonoscopy in Average-Risk Women Regional Navy/Army Medical Centers study (CONCeRN), comprising women undergoing complete colonoscopies. We individually matched women with adenoma (n=165 cases) to those without adenoma (n=311 controls). We extracted DNA using the Animal Tissue DNA Extraction Kit (AutoGene) and sequenced the V4 region of the 16S rRNA gene to characterize normal colonic mucosal bacteria, including alpha and beta diversity, taxonomic abundance, and co-abundance groups (CAGs). Fasting serum collected before colonoscopy underwent targeted quantitative liquid chromatography-tandem mass spectrometry to measure 13 primary and secondary BAs. We used multivariable conditional logistic regression, partial Pearson’s correlations, and linear regression to estimate interrelationships among the GM, BAs, and adenoma. Results: Multiple genera were statistically significantly associated with adenomas. For example, for the centered log-ratio transformed relative abundance of Phascolarctobacterium, Parvimonas, and Porphymonas, the ORs (95% CIs) were 0.75 (0.60-0.95, P=0.02), 0.71 (0.55-0.92; P=0.01), and 0.67 (0.49-0.93; P=0.02), respectively. A CAG comprising phylum Firmicutes, Actinobacteria, Proteobacteria, and Fusobacteria was less abundant among cases than controls (log2folddiff=-0.80, P=0.002). Alpha and beta diversity associations were close to null and not statistically significant. However, alpha diversity metrics were inversely associated with primary BAs [e.g., for Shannon (R2=-0.13, P=0.01)] and positively associated with secondary BAs [e.g., for Shannon (R2=0.16, P=0.001)]. Though no circulating BAs were statistically significantly associated with adenomas, those in the highest relative to lowest tertile of taurine-conjugated (TC) BAs, primary BAs, and secondary BAs had a 44% (95% CI: 0.85-2.46), 24% (95% CI: 0.73-2.12), and 11% (95% CI: 0.61-2.01) higher odds of adenoma, respectively. We found that TCBAs, primary BAs, and secondary BAs were inversely associated with the abundance of Parvimonas [e.g., for TCBAs (R2=-0.11, P=0.02)] and Porphyromonas [e.g., for TCBAs (R2=-0.11, P=0.02)]. Conclusions: We found short-chain fatty acid-producing and oral-originating bacteria were inversely associated with adenomas. Our oral bacteria findings are contrary to findings from prior studies. Our findings suggest potential interrelationships among the GM and BAs in adenoma development. Citation Format: Maria F. Gomez, Doratha A. Byrd, Stephanie R. Hogue, Jessica R. Burns, Nathan Smith, Joshua Sampson, Erikka Loftfield, Andrew Warner, Casey Dagnall, Kristine Jones, Belynda Hicks, Yunhu Wan, Youngchul Kim, Jin Xu, Rashmi Sinha, Emily Vogtmann. Associations of the mucosal microbiome and circulating bile acids with colorectal adenoma among average-risk women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3055.

Background Coffee consumption has been associated with a reduced risk of some cancers, but the evidence for renal cell carcinoma (RCC) is inconclusive. We investigated the relationship between coffee and RCC within a large cohort. Methods Coffee intake was assessed at baseline in the National Institutes of Health–American Association of Retired Persons Diet and Health Study. Among 420 118 participants eligible for analysis, 2674 incident cases were identified. We fitted Cox-regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee consumption vs non-drinkers. Results We observed HRs of 0.94 (95% CI 0.81, 1.09), 0.94 (0.81, 1.09), 0.80 (0.70, 0.92) and 0.77 (0.66, 0.90) for usual coffee intake of 10 years after baseline (HR 0.65, 95% CI 0.51, 0.82; Ptrend = 0.0005). Associations were similar between subgroups who drank predominately caffeinated or decaffeinated coffee (Pinteraction = 0.74). Conclusion In this investigation of coffee and RCC, to our knowledge the largest to date, we observed a 20% reduced risk for intake of ≥2 cups/day vs not drinking. Our findings add RCC to the growing list of cancers for which coffee consumption may be protective.

Background Human studies investigating the prospective relationship between microbial metabolites and colorectal cancer (CRC) risk are lacking. We tested whether higher serum bile acids (BAs) and lower short-chain fatty acids (SCFAs) were associated with CRC risk. Methods In baseline serum collected more than 30 years before a CRC diagnosis, we quantified concentrations of 15 BAs and 6 SCFAs using targeted liquid chromatography with tandem mass spectrometry assays in 1:1 matched cases and controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (men: n = 262 cases; women: n = 233 cases) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (men: n = 598 cases). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for BA and SCFA quartiles and summary measures with CRC overall and by anatomic location using multivariable conditional logistic regression models. PLCO analyses were stratified by sex. All statistical tests were 2-sided. Results In PLCO women, 7 BAs were strongly associated with increased CRC risk, including the secondary BAs, deoxycholic (ORQ4 v Q1 = 2.85, 95% CI = 1.45 to 5.60, Qtrend = 0.011), glycodeoxycholic (OR Q4 v Q1 = 3.45, 95% CI = 1.79 to 6.64, Qtrend = 0.006), taurodeoxycholic (OR Q4 v Q1 = 2.36, 95% CI = 1.22 to 4.55, Qtrend = 0.023), and glycolithocholic acid (ORQ4 v Q1 = 2.71, 95% CI = 1.41 to 5.22, Qtrend = 0.015). Women in the highest compared with lowest quartile of total SCFAs had a 45% lower risk of CRC (OR = 0.55, 95% CI = 0.31 to 0.98, Ptrend = .03). Associations for total BAs and SCFAs were strongest among women with proximal colon cancer. No statistically significant associations were observed for BA or SCFA measures among men. Conclusions Serum concentrations of BAs, particularly downstream microbial metabolites of cholic acid, were strongly associated with increased risk of CRC among women.

Consortium-based research is crucial for producing reliable, high-quality findings, but existing tools for consortium studies have important drawbacks with respect to data protection, ease of deployment, and analytical rigor. To address these concerns, we developed COnsortium of METabolomics Studies (COMETS) Analytics to support and streamline consortium-based analyses of metabolomics and other -omics data. The application requires no specialized expertise and can be run locally to guarantee data protection or through a Web-based server for convenience and speed. Unlike other Web-based tools, COMETS Analytics enables standardized analyses to be run across all cohorts, using an algorithmic, reproducible approach to diagnose, document, and fix model issues. This eliminates the time-consuming and potentially error-prone step of manually customizing models by cohort, helping to accelerate consortium-based projects and enhancing analytical reproducibility. We demonstrated that the application scales well by performing 2 data analyses in 45 cohort studies that together comprised measurements of 4,647 metabolites in up to 134,742 participants. COMETS Analytics performed well in this test, as judged by the minimal errors that analysts had in preparing data inputs and the successful execution of all models attempted. As metabolomics gathers momentum among biomedical and epidemiologic researchers, COMETS Analytics may be a useful tool for facilitating large-scale consortium-based research.

Background Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed because of measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk. Methods Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results Two metabolites displayed a dose-response association with self-reported alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54, 95% CI = 1.51 to 4.27) and pancreatic cancer (OR = 1.43, 95% CI = 1.03 to 1.99) in EPIC and liver cancer (OR = 2.00, 95% CI = 1.44 to 2.77) and liver disease mortality (OR = 2.16, 95% CI = 1.63 to 2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19, 95% CI = 1.60 to 2.98) in ATBC. Conclusions 2-hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.

Background Physical activity is associated with lower risk for endometrial cancer, but the extent to which the association is mediated by body mass index (BMI) in midlife is unclear. This study describes the physical activity–endometrial cancer association and whether BMI mediates this relationship. Methods Participants were 67 705 women in the National Institutes of Health-AARP Diet and Health Study (50-71 years) who recalled their physical activity patterns starting at age 15-18 years. We identified 5 long-term physical activity patterns between adolescence and cohort entry (ie, inactive, maintained low, maintained high, increasers, decreasers). We used Cox regression to assess the relationship between these patterns and midlife BMI and endometrial cancer, adjusting for covariates. Mediation analysis was used to estimate the proportion of the physical activity–endometrial cancer association that was mediated by midlife BMI. Results During an average 12.4 years of follow-up 1468 endometrial cancers occurred. Compared with long-term inactive women, women who maintained high or increased activity levels had a 19% to 26% lower risk for endometrial cancer (maintained high activity: hazard ratio = 0.81, 95% confidence interval [CI] = 0.67 to 0.98; increasers: hazard ratio = 0.74, 95% CI = 0.61 to 0.91). They also had a 50% to 77% lower risk for obesity in midlife (eg, maintained high activity: odds ratio for a BMI of 30-39.9 kg/m2 = 0.50, 95% CI = 0.46 to 0.55; and maintained high activity, odds ratio for a BMI of ≥40 kg/m2 = 0.32, 95% CI = 0.26 to 0.39). BMI was a statistically significant mediator accounting for 55.5% to 62.7% of the physical activity–endometrial cancer associations observed. Conclusions Both maintaining physical activity throughout adulthood and adopting activity later in adulthood can play a role in preventing obesity and lowering the risk for endometrial cancer.

Abstract Background: Laboratory and emerging epidemiologic data suggest that bile acids (BAs), major regulators of the gut microbiota, play an important role in liver disease and cancer etiology. However, few epidemiologic studies have comprehensively examined associations between BAs and either liver endpoints or biliary cancer. Methods: In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, we designed 1:1 matched nested case-control studies of primary liver cancer (n=247 cases), fatal liver disease (n=261 cases), and primary biliary cancer (n=92 cases). Using baseline serum collected ≤30 years prior to diagnosis or death, we measured concentrations of 15 BAs with liquid chromatography tandem mass spectrometry. We used multivariable conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between BAs and each endpoint, accounting for multiple comparisons. Results: Comparing the highest to the lowest quartile, ten BAs were positively associated with liver cancer risk, including taurocholic (OR =4.70, 95% CI=2.51-8.78; Q-trend1. Conclusion: Conjugated BAs were strongly associated with increased risk of liver cancer and fatal liver disease, suggesting mechanistic links between the gut microbiota, BA signaling pathways, and liver cancer or death from liver disease. Citation Format: Zeinab Farhat, Neal D. Freedman, Joshua N. Sampson, Roni T. Falk, Jill Koshiol, Stephanie J. Weinstein, Demetrius Albanes, Rashmi Sinha, Erikka Loftfield. A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2385.

Background: Bile acid (BA) and short chain fatty acid (SCFA) production is affected by diet and microbial metabolism. These metabolites may play important roles in human carcinogenesis. Methods: We used a fully quantitative targeted LC-MS/MS system to measure serum and fecal BA and SCFA concentrations in 136 Costa Rican adults at study baseline and 6-months. We randomly selected 50 participants and measured their baseline samples in duplicate. Our objective was to evaluate: Technical reproducibility; 6-month temporal variability; and concordance between sample type collected from the same individual at approximately the same time. Results: Technical reproducibility was excellent, with intraclass correlation coefficients (ICC) ≥0.83 for all BAs except serum tauroursodeoxycholic acid (ICC = 0.72) and fecal glycolithocholic acid (ICC = 0.66) and ICCs ≥0.81 for all SCFAs except serum 2-methylbutyric acid (ICC = 0.56) and serum isobutyric acid (ICC = 0.64). Temporal variability ICCs were generally low, but several BAs (i.e., deoxycholic, glycoursodeoxycholic, lithocholic, taurocholic, and tauroursodeoxycholic acid) and SCFAs (i.e., 2-methylbutyric, butyric, propionic, and valeric acid) had 6-month ICCs ≥0.44. The highest degree of concordance was observed for secondary and tertiary BAs. Conclusions: Serum and fecal BAs and SCFAs were reproducibly measured. However, 6-month ICCs were generally low, indicating that serial biospecimen collections would increase statistical power in etiologic studies. The low concordance for most serum and fecal metabolites suggests that consideration should be paid to treating these as proxies. Impact: Our findings will inform the design and interpretation of future human studies on associations of BAs, SCFAs, and potentially other microbial metabolites, with disease risk.

This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. For EPIC-Oxford, it is: Cancer Research UK C8221/A29017 and C8221/A19170, and Medical Research Council MR/M012190/1. RZ-R was supported by the “Miguel Servet” program (CP15/00100) from the Institute of Health Carlos III (Cofunded by the European Social Fund (ESF) - ESF investing in your future). This work was supported in part by the French National Cancer Institute (L’Institut National du Cancer; INCA; grant numbers 2009-139 and 2014-1-RT-02-CIRC-1; PI: M. Jenab). For pancreatic cancer in EPIC the work was supported by internal IARC funds., Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. The identification of biomarkers of habitual alcohol intake may enhance evidence on the role of alcohol in cancer onset. Methods: Untargeted metabolomics was used to identify metabolites correlated with habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n=454). Significant correlations were replicated in independent datasets of controls from casecontrol studies nested within EPIC (n=281) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n=438) study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals for associations of alcohol-associated metabolites and selfreported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results: Two metabolites displayed a dose-response association with alcohol intake: 2-hydroxy-3- methylbutyric acid and an unidentified compound (m/z(+):231.0839). A 1-SD increase in log2- transformed levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR=2.14; 1.39-3.31) and pancreatic cancer (OR=1.65; 1.17-2.32) in EPIC and liver cancer (OR=2.00; 1.44-2.77) and liver disease mortality (OR=2.16; 1.63-2.86) in ATBC. Conversely, a 1-SD increase in log2- transformed questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR=2.19; 1.60-2.98) in ATBC. Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies., Intramural Research Program of the National Cancer Institute at the National Institutes of Health, Cancer Research UK C8221/A29017 and C8221/A19170, Medical Research Council MR/M012190/1, “Miguel Servet” program (CP15/00100) from the Institute of Health Carlos III (Cofunded by the European Social Fund (ESF) - ESF investing in your future), French National Cancer Institute 2009-139 and 2014-1-RT-02-CIRC-1, IARC funds

Background: Surveillance of domain-specific physical activity in the United States is lacking. Thus, the authors describe domain-specific moderate to vigorous physical activity (MVPA) in a nationwide sample of US adults. Methods: Participants from the AmeriSpeak panel (n = 2649; 20–75 y; 50% female) completed the Activities Completed Over Time in 24-Hours previous-day recall. The authors estimated average MVPA duration (in hours per day) overall and in major life domains by sex, age, race/ethnicity, and education. They also described the most commonly reported MVPAs and timing of MVPA during the day. Results: Across all life domains, participants reported an average of 2.5 hours per day in MVPA. Most MVPA was accumulated during work (50% of total, 1.2 h/d) and household activities (28%, 0.7 h/d) with less MVPA reported in leisure time (15%, 0.4 h/d). Time reported in MVPA varied by sex, and race/ethnicity (P Conclusions: Work and household activities accounted for 78% of overall MVPA reported, while leisure-time MVPA accounted for only 15% of the total. Encouraging MVPA during leisure time and transportation remain important targets for promoting MVPA in US adults.

Background: Obesity is an established risk factor for multiple cancer types. Lower microbial richness has been linked to obesity, but human studies are inconsistent, and associations of early-life body mass index (BMI) with the fecal microbiome and metabolome are unknown. Methods: We characterized the fecal microbiome (n = 563) and metabolome (n = 340) in the Northern Finland Birth Cohort 1966 using 16S rRNA gene sequencing and untargeted metabolomics. We estimated associations of adult BMI and BMI history with microbial features and metabolites using linear regression and Spearman correlations (rs) and computed correlations between bacterial sequence variants and metabolites overall and by BMI category. Results: Microbial richness, including the number of sequence variants (rs = −0.21, P < 0.0001), decreased with increasing adult BMI but was not independently associated with BMI history. Adult BMI was associated with 56 metabolites but no bacterial genera. Significant correlations were observed between microbes in 5 bacterial phyla, including 18 bacterial genera, and metabolites in 49 of the 62 metabolic pathways evaluated. The genera with the strongest correlations with relative metabolite levels (positively and negatively) were Blautia, Oscillospira, and Ruminococcus in the Firmicutes phylum, but associations varied by adult BMI category. Conclusions: BMI is strongly related to fecal metabolite levels, and numerous associations between fecal microbial features and metabolite levels underscore the dynamic role of the gut microbiota in metabolism. Impact: Characterizing the associations between the fecal microbiome, the fecal metabolome, and BMI, both recent and early-life exposures, provides critical background information for future research on cancer prevention and etiology.