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Thermoelectric convection in a plane capacitor is investigated in a microgravity environment and in the case of the thermal stable and unstable stratification in terrestrial conditions. Energetic analysis shows that in the thermal stable stratification, the thermoelectric convection is delayed while in the thermal unstable stratification, it is enhanced by the Archimedean buoyancy before the latter takes over the dielectrophoretic buoyancy and drives natural thermal convection. An experiment in parabolic flights shows the formation of thermoelectric convection at the end of the microgravity phase.

Purpose: The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs, and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L).Methods: We investigated whether CYP2C9 genotype was associated with risk of colorectal adenoma and/or modified associations with aspirin treatment or cigarette smoking in a cohort of 928 participants in a randomized trial of aspirin chemoprevention. Generalized linear regression was used to compute relative risks (RRs) and 95 % confidence intervals (95 % CIs). Multiplicative interactions terms were used to assess effect modification.Results: CYP2C9 genotype was associated with increased risks for adenoma recurrence of 29 % (RR = 1.29, 95 % CI 1.09-1.51) for ≥1 variant allele (CYP2C9*2 or *3) and 47 % (RR = 1.47, 95 % CI 1.19-1.83) for ≥1 CYP2C9*3 allele. The risk for advanced lesions or multiple (≥3) adenomas was increased by 64 % (RR = 1.64, 95 % CI 1.18-2.28) for ≥1 variant allele (CYP2C9*2 or *3) and 79 % (RR = 1.79, 95 % CI 1.16-2.75) for ≥1 CYP2C9*3 allele. Genotype modified associations with smoking, but not aspirin treatment. The adenoma risk was increased by 26 % (RR = 1.26, 95 % CI 0.99-1.58) for former smokers and 60 % (RR = 1.60, 95 % CI 1.19-2.15) for current smokers among wild-type individuals, but there was no increased risk among individuals with ≥1 variant allele (CYP2C9*2 or *3) (p (interaction) = 0.04).Conclusions: Carriers of CYP2C9 variants with lower enzyme activity have increased overall risk of colorectal adenoma but reduced adenoma risk associated with cigarette smoking. These results may be due to effects on the synthesis of endogenous eicosanoids and/or reduced activation of procarcinogens in smoke by CYP2C9 variants. [ABSTRACT FROM AUTHOR]

Oxysterols are metabolites of cholesterol that regulate the homeostasis of cholesterol, fatty acids, and glucose. These metabolites are generated throughout the body, either enzymatically or from oxidative stress, and are detectable in peripheral circulation. We previously reported that circulating 27-hydroxycholesterol (27-OHC), an endogenous selective estrogen receptor modulator, may be a risk factor for colorectal adenomas. Here, in addition to 27-OHC, we report on four other circulating oxysterols: 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7ɑ-hydroxycholesterol, and 4β-hydroxycholesterol. Oxysterol concentrations were measured using liquid chromatography/mass spectrometry from fasting plasma collected at baseline from 1,246 participants of the Vitamin D/Calcium Polyp Prevention Study, a multicenter adenoma chemoprevention trial. To evaluate multiple oxysterols simultaneously, we used both log-linear regression and Bayesian kernel machine regression models developed for analyses of complex mixtures adjusted for potential confounding factors. Higher circulating 7ɑ-hydroxycholesterol was associated with higher adenoma risk (Bayesian kernel machine regression-based multivariable-adjusted risk ratios (RR; for the 75th vs. 25th percentile, 1.22; 95% credible interval, CI, 1.04-1.42). In contrast, higher circulating 4β-hydroxycholesterol was associated with lower risk of these polyps (RR, 0.84; 95% CI, 0.71-0.99). The positive association with advanced adenoma risk that we previously reported for circulating 27-OHC persisted when controlling for other oxysterols (RR, 1.26; 95% CI, 0.98-1.62), including among those with advanced adenomas at baseline (RR, 1.75; 95% CI, 1.01-3.06). Prevention Relevance: Circulating concentrations of multiple oxysterols measured at the time of an initial colorectal adenoma diagnosis may be risk factors for subsequent incidence of these lesions. Novel colorectal cancer prevention strategies may target oxysterol formation., (©2024 American Association for Cancer Research.)

The incidence of colorectal cancer (CRC) among individuals under age 50, or early-onset CRC (EOCRC), has been rising over the past few decades for unclear reasons, and the etiology of the disease remains largely unknown. Known genetic risk factors do not explain this increase, pointing to possible environmental and as-yet unidentified genetic contributors and their interactions. Previous research linked genetic variation on chromosome 6 to increased CRC risk. This region harbors multiple immune genes, including the gene encoding Major Histocompatibility Complex (MHC) class I polypeptide-related sequence A (MICA). MICA is a polygenic ligand for the Natural Killer Group 2D receptor (NKG2D), a receptor expressed on Natural Killer (NK) cells and other lymphocytes. Given that intra-tumoral NK cell infiltration correlates with favorable CRC outcomes, we hypothesized that germline genetic variation in MICA could influence CRC risk. In a discovery set of 40,125 cases and controls, we show that the minor G allele at Chr6:31373718C>G (hg19) is associated with increased risk for CRC (odds ratio (OR) = 1.09, 95% confidence interval (CI) 1.04 - 1.15, p = 0.0009). The effect is stronger in EOCRC (OR = 1.26, 95% CI 1.08 - 1.44, p = 0.0023) than in those 50 and over (OR = 1.07, 95% CI 1.02 - 1.13; p = 0.012) (Ratio of ORs = 1.32, 95% CI 1.14 - 1.52, p = 0.0002). In an independent validation set of 77,983 cases and controls, the adjusted interaction by age-of-onset was significant at OR = 1.15 (95% CI 1.03 - 1.34, p = 0.0150) with a higher risk in EOCRC. Expression quantitative trait locus analysis in normal colonic epithelia showed that MICA RNA expression decreases linearly with each additional copy of the minor G allele (p = 3.345 × 10e-18). Bulk RNA analysis of the tumor immune microenvironment revealed that tumors from patients with CG or GG genotypes have lower resting and activated NK cell infiltration as compared to tumors from patients with CC genotype. Multiplex immunofluorescence analysis demonstrated that patients with a G allele (i.e. CG or GG genotype, but not CC genotype) have a statistically significant decrease in the number of NK cells in tumor compared to adjacent normal colonic mucosa. Taken together, population-based epidemiologic, molecular, genetic, cellular and immunologic evidence demonstrate that MICA genotype is associated with increased risk of EOCRC and reduced number of NK cells in colorectal tumors, suggesting that patients with a G allele have altered NK cell-mediated immunosurveillance. These novel findings suggest that EOCRC may have a previously unrecognized innate immune-mediated etiology which merits further investigation.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC., Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk., Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO)., Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10 -8 ) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10 -8 ). No interactions were observed for dietary and total folate., Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis., Methods: 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 (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test)., Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - OR AA : 1.62, 95% CI: 1.34-1.96; OR AG : 1.41, 95% CI: 1.30-1.54; OR GG : 1.22, 95% CI: 1.13-1.31; p-value 3-d.f. : 5.46 × 10 -11 ) and 13q14.13 (rs9526201, LRCH1 - OR GG : 2.11, 95% CI: 1.56-2.83; OR GA : 1.52, 95% CI: 1.38-1.68; OR AA : 1.13, 95% CI: 1.06-1.21; p-value 2-d.f. : 7.84 × 10 -09 )., Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship., (© 2023. The Author(s).)

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer., Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Variants in the vitamin D-binding protein (DBP) gene (GC) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D3 and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies., Objective: To estimate supplemental vitamin D3 and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, DBP1f, DBP2) encoded by 2 missense variants: rs7041 (NG&#95;012837.3:g.57904T>G NP&#95;001191235.1:p.Asp432Glu) and rs4588 (NG&#95;012837.3:g.57915C>A NP&#95;001191235.1:p.Thr436Lys)., Design, Setting, and Participants: Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial of 2259 participants with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy in the US from July 1, 2004, to August 31, 2013. The current analyses were performed from August 12, 2019, to July 16, 2022., Interventions: Daily vitamin D3 (1000 IU), calcium (1200 mg), both, or placebo., Main Outcomes and Measures: One or more adenomas diagnosed during 3 to 5 years of follow-up. Treatment effects were estimated according to DBP isoform as risk ratios (RRs) and 95% CIs using Poisson regression analysis., Results: Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants (chosen to avoid population stratification bias) were included in the analysis. Among those with the DBP2 isoform (rs4588*AC or AA), the RRs (95% CI) for adenoma recurrence were 0.84 (0.72-1.00) with vitamin D3 relative to no vitamin D3, 0.83 (95% CI, 0.70-0.99) with calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) with both agents relative to neither agent. Conversely, among those without DBP2 (rs4588*CC), the corresponding values were 1.08 (95% CI, 0.93-1.26; P = .03 for interaction) with vitamin D3 relative to no vitamin D3, 0.98 (95% CI, 0.84-1.14; P = .37 for interaction) with calcium relative to no calcium, and 1.09 (0.88-1.36; P = .03 for interaction) with both agents relative to neither agent. Among DBP2 homozygotes (rs4588*AA), the RR for adenoma recurrence was 0.57 (95% CI, 0.31-1.08) with both agents relative to neither agent., Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform-encoding rs4588*A allele may particularly benefit from vitamin D3 and/or calcium supplementation for colorectal adenoma prevention., Trial Registration: ClinicalTrials.gov Identifier: NCT00153816.

Background: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance., Methods: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group)., Results: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity., Conclusions: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort., Impact: The proposed model has potential utility in risk-stratified colorectal cancer prevention., (©2023 American Association for Cancer Research.)

Bariatric surgery is associated with weight loss attributed to reduced caloric intake, mechanical changes, and alterations in gut hormones. However, some studies have suggested a heightened incidence of colorectal cancer (CRC) has been associated with bariatric surgery, emphasizing the importance of identifying mechanisms of risk. The objective of this study was to determine if bariatric surgery is associated with decreases in fecal short-chain fatty acids (SCFA), a group of bacterial metabolites of fiber. Fecal samples ( n = 22) were collected pre- (~6 weeks) and post-bariatric surgery (~4 months) in patients undergoing Roux-en-Y gastric bypass and sleeve gastrectomy. SCFA levels were quantified using liquid chromatography/mass spectrometry. Dietary intake was quantified using 24-h dietary recalls. Using an aggregate variable, straight SCFAs significantly decreased by 27% from pre- to post-surgery, specifically acetate, propionate, butyrate, and valerate. Pre-surgery weight was inversely associated with butyrate, with no association remaining post-surgery. Multiple food groups were positively (sugars, milk, and red and orange vegetables) and inversely (animal protein) associated with SCFA levels. Our results suggest a potential mechanism linking dietary intake and SCFA levels with CRC risk post-bariatric surgery with implications for interventions to increase SCFA levels.

Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time., Prevention Relevance: This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer., (©2022 American Association for Cancer Research.)

Background: Serrated polyps (SP) are important colorectal cancer precursors, yet their epidemiology is incompletely understood. We measured risk factors for incident sessile-serrated lesions (SSL) and microvesicular (MVHP) and goblet-cell rich (GCHP) hyperplastic polyp subtypes., Methods: We conducted a cohort study of patients undergoing colonoscopic surveillance nested within a chemoprevention trial. Outcomes of interest were ≥1 SPs, including SSLs, MVHPs, and GCHPs specifically. Multivariable generalized estimating equation models were used to estimate adjusted risk ratios (RR) and 95% confidence intervals (CI) for different polyp types., Results: Among 2,102 participants, a total of 1,615 SPs (including 212 SSLs) were found among 758 participants during follow-up. Prior history of SPs was strongly associated with subsequent occurrence of SPs. There was no apparent association between age, sex, or education and risk of SPs. Black participants were at lower risk of SSLs and MVHPs, but higher risk of GCHPs compared with white participants [RR, 0.40; 95% CI, 0.16-0.99); RR, 0.63 (95% CI, 0.42-0.96); and RR, 1.83 (95% CI, 1.23-2.72) respectively]. Alcohol and smoking exposure were also associated with SPs, including hyperplastic polyp subtypes in particular., Conclusions: In this prospective study, the risk of SP subtypes differed by race, alcohol, and smoking status, and prior history of SPs. Risk factor associations for SPs differ from risk factors for conventional adenomas, supporting the concept of etiologic heterogeneity of colorectal cancer., Impact: These findings allow for better risk stratification of patients undergoing colorectal cancer screening and could inform screening test selection., (©2022 American Association for Cancer Research.)

Backgound: Circulating oxysterols, cholesterol metabolites with important signaling functions, are increasingly being recognized as candidate biomarkers for several diseases, but associations with demographic and health characteristics remain poorly described., Objective: This study aims to characterize associations of major circulating oxysterols with sex, age, race/ethnicity, body mass index (BMI), lifestyle factors, and use of common medications., Methods: We measured plasma concentrations of 27-hydroxycholesterol (27-OHC), 25-hydroxycholesterol (25-OHC), 24(S)-hydroxycholesterol (24(S)-OHC), 7ɑ-hydroxycholesterol (7ɑ-OHC), and 4β-hydroxycholesterol (4β-OHC) from 1,440 participants of a completed clinical trial for the chemoprevention of colorectal adenomas. Adjusted percent difference in means were calculated using linear regression., Results: Women had 18% (95% CI, 14%, 22%) lower 27-OHC and 21% (15%, 27%) higher 4β-OHC than men. Blacks had 15% (7%, 23%) higher 4β-OHC than Non-Hispanic Whites, and Asian or Pacific Islanders had 19% (2%, 35%) higher 7ɑ-OHC than Non-Hispanic Whites. Individuals of BMI ≥35 kg/m 2 had 33% (25%, 41%) lower 4β-OHC than those <25 kg/m 2 . Current smokers had 15% (5%, 24%) higher 7ɑ-OHC than never smokers, and daily alcohol drinkers had 17% (10%, 24%) higher 7ɑ-OHC than never drinkers. Statin use was associated with lower concentrations of all 5 oxysterols. Differences in mean <15% were found for characteristics such as age, total dietary energy intake, physical activity, diabetes, and anti-inflammatory drug use., Conclusion: Circulating oxysterols are uniquely associated with multiple demographic and health characteristics., (Copyright © 2022. Published by Elsevier Inc.)

Background: Sex hormones have been implicated in the etiology of colorectal neoplasia in women for over 40 years, but there has been very little investigation of the role of these hormones in men., Methods: Using data from an adenoma chemoprevention trial, we conducted a secondary analysis to examine serum hormone levels [testosterone, androstenedione, DHEA sulfate (DHEAS), and sex hormone binding globulin (SHBG)] and risk of colorectal precursors in 925 men. Multivariable logistic regression models were fit to evaluate adjusted associations between hormone levels and risk of "low-risk" (single tubular adenoma < 1 cm) and "high-risk" lesions (advanced adenoma or sessile serrated adenoma or right-sided serrated polyp or >2 adenomas of any size)., Results: Overall, levels of free testosterone, total testosterone, androstenedione, DHEAS, or SHBG were not associated with either "low-risk" or "high-risk" early precursor lesions in the colorectum., Conclusions: These findings do not support the role of sex hormones in early colorectal neoplasia among men., Impact: This large prospective study address a missing gap in knowledge by providing information on the role of sex hormones in colorectal neoplasia in males., (©2021 American Association for Cancer Research.)

Background: Adenomas and serrated lesions represent heterogeneous sets of early precursors in the colorectum with varying malignant potential. They are often distinguished by their histopathologic differences, but little is known about potential differences in regulation of epithelial proliferation and apoptosis., Methods: We conducted a protein expression analysis using tissue microarrays of 625 colorectal adenomas and 142 serrated lesions to determine potential differences in regulation of epithelial proliferation and apoptosis. We quantitated proliferation with Ki-67; apoptosis with activated caspase-3 (CASP3); up- and down-regulators of proliferation with cyclin D1, p16INK2, and p21Cip1; and apoptosis regulators with BAX, BCL2, and survivin. Linear mixed effects models and circos diagrams were used to determine relationships among expression and lesion characteristics., Results: Adenomas had a significantly higher CASP-3 labeling index (LI) than serrated lesions, resulting in a lower net growth ratio (Ki-67 LI/activated CASP-3 LI, p-value<0.0001). Cyclin D1 LI, p16 LI and p21 LI were lower in adenomas compared to serrated lesions, while expression of both BCL2 and BAX were higher (p <0.001). Among adenomas, cyclin D1 LI and p16 LI levels increased with greater villous component, and the highest BAX expression was detected in adenomas larger than 2 cm (both p<0.0001). Right-sided adenomas had higher CASP3 LI than left colorectal adenomas (p = 0.008). Significant differences in cyclin D1 LI, p21 LI and survivin LI were also observed across histopathologic subtypes of serrated lesions., Conclusions: Our findings demonstrate different patterns of regulatory protein expression in adenomas than serrated lesions, especially involving apoptosis. ClinicalTrials.gov Identifier: NCT00272324., Competing Interests: The authors have declared that no competing interests exist.

Background: Antibiotics may increase colorectal neoplasia risk by modifying the gut microbiome. It is unknown whether use is associated with the risk of new colorectal adenomas among individuals with prior adenomas., Methods: We performed a secondary analysis of four randomized clinical trials for the chemoprevention of colorectal adenomas. Participants self-reported all currently used prescription drugs shortly after an initial colorectal adenoma diagnosis and two or three times a year thereafter over 3 to 5 years of follow-up. We estimated adjusted risk ratios (RR) with 95% confidence intervals (CI) for incident adenomas, analyzing the four trials together., Results: Cumulatively, the four trials enrolled 5,174 participants (3,491 men and 1,683 women), of whom 4,769 (92%) completed ≥1 follow-up colonoscopy. A total of 763 (15%) participants reported using oral antibiotics on ≥2 occasions. Overall, 39% of those using oral antibiotics at least twice developed new colorectal adenomas compared with 40% of those with no use or a single report of use (RR, 0.99; 95% CI, 0.90-1.10). No statistically significant associations were found in study-specific analyses, and results were similar for high- and low-risk adenoma findings, antibiotic class, anatomic location of adenomas, and analyses excluding those with interim colorectal exams., Conclusions: Oral antibiotic use during colonoscopic surveillance after an initial adenoma diagnosis was not associated with risk of these polyps., Impact: Any changes to the gut microbiome as a consequence of oral antibiotic use during surveillance may not affect the development of metachronous colorectal adenomas., (©2021 American Association for Cancer Research.)

The oxysterol 27-hydroxycholesterol (27-OHC) is an endogenous selective estrogen receptor modulator implicated in breast cancer etiology. It is unknown whether circulating 27-OHC is associated with colorectal neoplasia risk. Circulating 27-OHC was measured using LC/MS in fasting plasma collected at baseline from participants of the Vitamin D/Calcium Polyp Prevention Study, a completed randomized clinical trial. Participants were between 45 and 75 years old, recently diagnosed with ≥1 colorectal adenoma, and followed for new colorectal polyps during colonoscopic surveillance. Adjusted risk ratios (RR) with 95% confidence intervals (CI) of new colorectal polyps were estimated for quartiles of circulating 27-OHC using log-linear regression for repeated outcomes. Polyp phenotypes included any adenomas, advanced adenomas, hyperplastic polyps, and sessile serrated adenomas/polyps. Circulating 27-OHC was measured at baseline for 1,246 participants. Compared with participants with circulating 27-OHC below the first quartile (<138 ng/mL), those with circulating 27-OHC at or above the fourth quartile (≥201 ng/mL) had 24% higher risk of adenomas (RR, 1.24; 95% CI, 1.05-1.47) and 89% higher risk of advanced adenomas (RR, 1.89; 95% CI, 1.17-3.06). Stronger associations were observed among participants with advanced adenomas at baseline. Circulating 27-OHC was not associated with risk of hyperplastic polyps (RR, 0.90; 95% CI, 0.66-1.22) or sessile serrated adenomas/polyps (RR, 1.02; 95% CI, 0.50-2.07). Circulating 27-OHC may be a risk factor for colorectal adenomas but not serrated polyps. PREVENTION RELEVANCE: This study found that plasma concentration of 27-hydroxycholesterol, a metabolite of cholesterol that regulates lipid metabolism and acts as a selective estrogen receptor modulator, is associated with the risk of developing precursor lesions for colorectal cancer., (©2021 American Association for Cancer Research.)

Gut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D 3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D 3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women ( P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none ( P trend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m 2 relative to those with a BMI < 22.5 kg/m 2 ( P trend = 0.17). Our results suggest that daily supplemental vitamin D 3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3-5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability. PREVENTION RELEVANCE: Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies., (©2020 American Association for Cancer Research.)

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group ( P = 0.001), 46% in the calcium group ( P = 0.002), and 34% in the calcium + vitamin D group ( P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 ( GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% ( P = 0.0006), 75% ( P = 0.0002), and 60% ( P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer., (©2020 American Association for Cancer Research.)

Background: It is unknown whether dietary supplementation with vitamin D or calcium prevents keratinocyte carcinomas, also known as nonmelanoma skin cancers., Objectives: This study aimed to determine whether daily vitamin D or calcium supplementation alters the risk of basal cell carcinoma (BCC) or invasive cutaneous squamous cell carcinoma (SCC)., Methods: The Vitamin D/Calcium Polyp Prevention Study is a completed multicenter, double-blind, placebo-controlled, partial 2 × 2 factorial, randomized clinical trial of vitamin D, calcium, or both for the prevention of colorectal adenomas. During 2004-2008, a total of 2259 men and women, 45-75 y of age, recently diagnosed with a colorectal adenoma, were randomly assigned to 1000 IU/d of vitamin D3 or placebo and 1200 mg/d of calcium carbonate or placebo for 3 or 5 y, and followed after treatment ended. Reports of incident BCC or SCC were confirmed from pathology records., Results: During a median follow-up of 8 y, 200 (9%) participants were diagnosed with BCC and 68 (3%) participants were diagnosed with SCC. BCC incidence was unrelated to treatment with vitamin D compared with no vitamin D (HR: 0.96; 95% CI: 0.73, 1.26), calcium compared with no calcium (HR: 1.01; 95% CI: 0.74, 1.39), and both agents compared with neither (HR: 0.99; 95% CI: 0.65, 1.51). SCC incidence was unrelated to treatment with vitamin D compared with no vitamin D (HR: 0.79; 95% CI: 0.49, 1.27), but there was suggestive evidence of beneficial treatment effects for calcium compared with no calcium (HR: 0.60; 95% CI: 0.36, 1.01) and both agents compared with neither (HR: 0.42; 95% CI: 0.19, 0.91)., Conclusions: Calcium alone or in combination with vitamin D may reduce the risk of SCC, but not BCC. This trial was registered at clinicaltrials.gov as NCT00153816., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Society for Nutrition.)

Although substantial evidence supports aspirin's efficacy in colorectal cancer chemoprevention, key molecular mechanisms are uncertain. An untargeted metabolomics approach with high-resolution mass spectrometry was used to elucidate metabolic effects of aspirin treatment in human colon tissue. We measured 10,269 metabolic features in normal mucosal biopsies collected at colonoscopy after approximately 3 years of randomized treatment with placebo, 81 or 325 mg/day aspirin from 325 participants in the Aspirin/Folate Polyp Prevention Study. Linear regression was used to identify aspirin-associated metabolic features and network analysis was used to identify pathways and predict metabolite identities. Poisson regression was used to examine metabolic features associations with colorectal adenoma risk. We detected 471 aspirin-associated metabolic features. Aside from the carnitine shuttle, aspirin-associated metabolic pathways were largely distinct for 81 mg aspirin (e.g., pyrimidine metabolism) and 325 mg (e.g., arachidonic acid metabolism). Among aspirin-associated metabolic features, we discovered three that were associated with adenoma risk and could contribute to the chemopreventive effect of aspirin treatment, and which have also previously been associated with colorectal cancer: creatinine, glycerol 3-phosphate, and linoleate. The last two of these are in the glycerophospholipid metabolism pathway, which was associated with 81 mg aspirin treatment and provides precursors for the synthesis of eicosanoids from arachidonic acid upstream of cyclooxygenase inhibition by aspirin. Conversely, carnitine shuttle metabolites were increased with aspirin treatment and associated with increased adenoma risk. Thus, our untargeted metabolomics approach has identified novel metabolites and pathways that may underlie the effects of aspirin during early colorectal carcinogenesis., (©2020 American Association for Cancer Research.)

Importance: Histologic classification of colorectal polyps plays a critical role in screening for colorectal cancer and care of affected patients. An accurate and automated algorithm for the classification of colorectal polyps on digitized histopathologic slides could benefit practitioners and patients., Objective: To evaluate the performance and generalizability of a deep neural network for colorectal polyp classification on histopathologic slide images using a multi-institutional data set., Design, Setting, and Participants: This prognostic study used histopathologic slides collected from January 1, 2016, to June 31, 2016, from Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, with 326 slides used for training, 157 slides for an internal data set, and 25 for a validation set. For the external data set, 238 slides for 179 distinct patients were obtained from 24 institutions across 13 US states. Data analysis was performed from April 9 to November 23, 2019., Main Outcomes and Measures: Accuracy, sensitivity, and specificity of the model to classify 4 major colorectal polyp types: tubular adenoma, tubulovillous or villous adenoma, hyperplastic polyp, and sessile serrated adenoma. Performance was compared with that of local pathologists' at the point of care identified from corresponding pathology laboratories., Results: For the internal evaluation on the 157 slides with ground truth labels from 5 pathologists, the deep neural network had a mean accuracy of 93.5% (95% CI, 89.6%-97.4%) compared with local pathologists' accuracy of 91.4% (95% CI, 87.0%-95.8%). On the external test set of 238 slides with ground truth labels from 5 pathologists, the deep neural network achieved an accuracy of 87.0% (95% CI, 82.7%-91.3%), which was comparable with local pathologists' accuracy of 86.6% (95% CI, 82.3%-90.9%)., Conclusions and Relevance: The findings suggest that this model may assist pathologists by improving the diagnostic efficiency, reproducibility, and accuracy of colorectal cancer screenings.

Background: The Aspirin/Folate Polyp Prevention Study previously found folic acid increased risk of advanced and multiple colorectal adenomas during a surveillance colonoscopy interval starting about 3 y after randomization., Objective: We conducted secondary analyses to evaluate folic acid effects with additional follow-up after treatment was stopped., Methods: In total, 1021 participants recently diagnosed with colorectal adenomas were randomly assigned to 1 mg/d of folic acid (n = 516) or placebo (n = 505), with or without aspirin, beginning 6 July 1994. The original 3-y treatment period was extended into a subsequent colonoscopy interval, but eventually stopped prematurely on 1 October 2004. With additional post-treatment follow-up, a total of 663 participants who extended treatment completed a second colonoscopic surveillance interval after the initial 3-y follow-up. In addition, 490 participants provided information regarding a subsequent surveillance colonoscopy occurring before completion of follow-up on 31 May 2012, including 325 who had agreed to extended treatment. Study endpoints included conventional adenomas, sessile serrated adenomas/polyps (SSA/Ps), or colorectal cancer, and RRs with 95% CIs were adjusted for baseline characteristics associated with availability of follow-up., Results: Among those who extended treatment, any colorectal neoplasia was found in 118 (36%) participants assigned to placebo and 146 (43%) assigned to folic acid during the second surveillance interval (RR: 1.21; 95% CI: 0.99, 1.47; P = 0.06). Increased risk of SSA/P with extended folic acid supplementation was statistically significant during the second surveillance interval (RR: 1.94; 95% CI: 1.02, 3.68; P = 0.04). There was no evidence of post-treatment effects for any colorectal neoplasia (RR: 1.01; 95% CI: 0.80, 1.28; P = 0.94), and the post-treatment effect for SSA/P was no longer statistically significant (RR: 1.38; 95% CI: 0.59, 3.19; P = 0.46)., Conclusions: Delayed treatment effects were not observed, but folic acid may increase SSA/P risk. This trial was registered at clinicaltrials.gov as NCT00272324., (Copyright © American Society for Nutrition 2019.)

The physical gut barrier, comprised of a thick mucus layer and the epithelium, plays an important role in defense against microbes and foreign antigens. Calcium and vitamin D may be involved in maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which may lead to endotoxemia and inflammation, and contribute to colorectal carcinogenesis. We investigated supplemental calcium (1200 mg, daily) and/or vitamin D 3 (1000 IU daily) effects on intestinal barrier function-related biomarkers in a subset of 105 participants from a large colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of the tight junction proteins claudin-1 (CLDN1), occludin (OCLD), and mucin-12 (MUC12) in the normal-appearing colorectal mucosa using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, in the calcium relative to the no calcium group, the CLDN1, OCLD, and MUC12 expression increased by 14% (P = 0.17), 23% (P = 0.11), and 22% (P = 0.07), respectively. In secondary analyses, the estimated calcium treatment effects were greater among participants with baseline serum 25-OH-vitamin D concentrations below the median value of 22.69 ng/mL (CLDN1: 29%, P = 0.04; OCLD: 36%, P = 0.06; MUC12: 35%, P = 0.05). There were no biomarker expression changes in the vitamin D 3 alone group; however, modest increases were found in the combined calcium/vitamin D 3 group. At baseline, obesity, history of a sessile-serrated adenoma, colorectal MIB-1/Ki-67 expression, and a family history of colorectal cancer were associated with CLDN1, OCLD, and MUC12 expression. Our study supports continued investigation of factors that could affect intestinal mucosal barrier integrity relevant to colorectal carcinogenesis., (© 2019 Wiley Periodicals, Inc.)

Background: Visceral adiposity is a risk factor for colorectal adenomas, and aspirin is an established chemopreventive agent. Evidence from clinical trials suggests the effectiveness of aspirin at preventing cardiovascular disease and cancer may require higher doses for higher body weight., Methods: Body mass index, body surface area, fat-free mass, and fat mass were calculated from baseline height and weight in 1,121 participants of the Aspirin/Folate Polyp Prevention Study, a double-blind, placebo-controlled, 3 × 2 factorial randomized clinical trial of low-dose (81 mg/day) or high-dose (325 mg/day) aspirin and/or 1 mg/day folic acid to prevent metachronous colorectal adenomas. Participants were treated during a surveillance colonoscopy interval of approximately 3 years. Risk ratios (RR) with 95% confidence intervals (CI) for any colorectal neoplasia and high-risk adenoma (HRA, advanced or ≥3 adenomas) were estimated from log-linear regression., Results: We did not find evidence to suggest aspirin dose-response differed by body composition measurements, including weight alone. Among those weighing ≥ 80 kg, treatment effects for low-dose aspirin (RR for colorectal neoplasia, 0.75; 95% CI, 0.60-0.94; RR for HRA, 0.52; 95% CI, 0.31-0.86) and high-dose aspirin (RR for colorectal neoplasia, 0.88; 95% CI, 0.72-1.08; RR for HRA, 0.68; 95% CI, 0.43-1.09) were not meaningfully different than for those weighing 70-79 kg or <70 kg., Conclusions: Measurements of body composition calculated from height and weight did not modify aspirin treatment effects for colorectal adenoma prevention., Impact: Aspirin dosing strategies accounting for body weight suggested in previous trials of colorectal cancer may not apply to adenomas., (©2019 American Association for Cancer Research.)

Vitamin D and calcium supplementation are postulated to have chemopreventive effects against colorectal neoplasia, yet in our previously reported randomized trial, there was no overall efficacy of calcium and/or vitamin D 3 against colorectal adenoma recurrence. It is possible vitamin D 3 and calcium chemopreventive effects are not detectable until beyond the 3- to 5-year follow-up captured in that trial. Accordingly, we explored possible vitamin D and calcium effects on posttreatment (observational) adenoma occurrence. In this secondary analysis of the observational follow-up phase of the Vitamin D/Calcium Polyp Prevention Study, participants who completed the treatment phase were invited to be followed for one additional surveillance colonoscopy cycle. We evaluated adenoma occurrence risk at surveillance colonoscopy, with a mean of 55 ± 15 months after treatment follow-up, according to randomized treatment with vitamin D versus no vitamin D, calcium versus no calcium, and calcium plus vitamin D versus calcium alone. Secondary outcomes included advanced and multiple adenomas. Among the 1,121 participants with observational follow-up, the relative risk (95% confidence interval, CI) of any adenoma was 1.04 (0.93-1.17) for vitamin D versus no vitamin D; 0.95 (0.84-1.08) for calcium versus no calcium; 1.07 (0.91-1.25) for calcium plus vitamin D versus calcium; and 0.96 (0.81-1.15) for calcium plus vitamin D versus neither. Risks of advanced or multiple adenomas also did not differ by treatment. Our results do not support an association between supplemental calcium and/or vitamin D 3 for 3 to 5 years and risk of recurrent colorectal adenoma at an average of 4.6 years after treatment., (©2019 American Association for Cancer Research.)

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ 1 (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 D 3 (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 D 3 and vitamin D 3 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), TGFβ 1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFβ 1 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 D 3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ 1 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, TGFβ 1 alone, and TGFα relative to TGFβ 1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms., (© 2018 Wiley Periodicals, Inc.)

Objective: Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically., Design: Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D 3 , both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models., Results: SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively)., Conclusion: In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6-10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. : Trial registration NUMBER: NCT00153816; Results., Competing Interests: Competing interests: None of the authors report conflicts of interest related to this article. Full disclosures are as follows: SDC: Research funding from Exact Sciences, ColoWrap and Boston Scientific. DJA: Scientific Advisory Board for Cancer Prevention Pharmaceuticals, Speakers Bureau for Ambry Genetics. DJR: Scientific Advisory Board for Medtronic and Consultant for Freenome. CAB: Research funding from Cancer Prevention Pharmaceuticals. JAB: Together with Dartmouth College, JAB: holds a use patent for the chemopreventive use of calcium, currently not licensed., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk., Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided., Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0., Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Calcium supplementation (1,200 mg/day) did not significantly reduce colorectal adenomas in our recent randomized, controlled trial (Vitamin D/Calcium Polyp Prevention Study, VCPPS, 2004-2013) in contrast to our previous trial (Calcium Polyp Prevention Study, CPPS, 1988-1996). To reconcile these findings, we identified participant characteristics that differed between the study populations and modified the effect of calcium supplementation on adenomas or high-risk findings (advanced or multiple adenomas). Compared to the CPPS, more participants in the VCPPS were obese (body mass index (BMI) ≥30 kg/m 2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI <25 kg/m 2 ; 18.5% vs. 31%). BMI appeared to modify the effect of calcium supplementation on adenomas and especially on high risk-findings: in the VCPPS, there was a 44% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.56, 95% CI = 0.26-1.23), but not among overweight (RR = 1.09, 95% CI = 0.62-1.91) or obese (RR = 1.54, 95% CI = 0.92-2.57) individuals (p interaction = 0.03). Similarly, in the CPPS, there was a 56% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.44, 95% CI = 0.26-0.74), but not among overweight (RR = 0.87, 95% CI = 0.55-1.39) or obese (RR = 1.02, 95% CI = 0.57-1.82) individuals (p interaction = 0.02). Standardization of each trial's findings to the BMI distribution in the other attenuated calcium's protective effect on adenomas in the CPPS but enhanced it in the VCPPS. In conclusion, 1,200 mg/day calcium supplementation may reduce risk of colorectal adenomas among those with normal BMI but not in overweight or obese individuals; and differences in BMI distribution partially account for the apparent difference in calcium efficacy between the two trials., (© 2018 UICC.)

To clarify the roles of vitamin D and calcium as potential chemopreventive agents against colorectal cancer in humans, and to develop "treatable", pre-neoplastic, phenotypic biomarkers of risk for colorectal neoplasms, we estimated the effects of supplemental vitamin D3 (1,000 IU/day [25 μg/day]) and calcium (1,200 mg/day), alone and in combination, on biomarkers of proliferation (mib-1), differentiation (p21), and apoptosis (bax [apoptosis-promoting] and bcl-2 [apoptosis-inhibiting]), in the normal-appearing rectal mucosa in a subsample of participants (n = 104) in a larger randomized, double-blind, placebo-controlled clinical trial among colorectal adenoma patients. The biomarkers were measured in rectal biopsies at baseline and after one year of follow up, using automated immunohistochemistry and quantitative image analysis. In the vitamin D plus calcium group relative to control, in the crypt differentiation zone (upper 40% of crypts), mib-1 expression decreased 24% (P = 0.28); p21 expression alone and relative to mib-1 expression increased 29% (P = 0.06) and 73% (P = 0.06), respectively; and bax expression relative to mib-1 expression increased 58% (P = 0.21). The estimated vitamin D alone treatment effects were similar but of lesser magnitudes, and those for calcium alone were mixed. All estimated treatment effects on bcl-2 expression were close to the null. These pilot study results support further investigation of whether 1) vitamin D and calcium promote colorectal epithelial cell differentiation, reduce proliferation, and promote apoptosis in the normal-appearing human colorectal mucosa, 2) vitamin D and calcium act as chemopreventive agents against colorectal neoplasms, and 3) mib-1, p21, and bax are potential "treatable", pre-neoplastic, biomarkers of risk for colorectal neoplasms., Competing Interests: The authors have declared that no competing interests exist.

Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D 3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/β (pIKKα/β), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/β expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/β. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/β expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707-16. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Aspirin may reduce the risk of several types of cancer., Objectives: To evaluate if folic acid is associated with risk of basal cell carcinoma (BCC)., Methods: BCC incidence was evaluated in a randomized, double-blind, placebo-controlled clinical trial of aspirin (81 mg daily or 325 mg daily for ~3 years) and/or folic acid (1 mg daily for ~6 years) for the prevention of colorectal adenomas among 1121 participants with a previous adenoma. BCC was confirmed by blinded review of pathology reports., Results: One hundred and four of 958 non-Hispanic white participants were diagnosed with BCC over a median follow-up of 13·5 years. Cumulative incidence of BCC was 12% [95% confidence interval (CI) 7-17] for placebo, 16% (95% CI 11-21) for 81 mg aspirin daily and 15% (95% CI 10-20) for 325 mg aspirin daily [hazard ratio (HR) for any aspirin 1·45 (95% CI 0·93-2·26); HR for 81 mg daily 1·57 (95% CI 0·96-2·56); HR for 325 mg daily 1·33 (95% CI 0·80-2·20)]. BCC risk was higher with aspirin use in those without previous skin cancer but lower with aspirin use in those with previous skin cancer (P interaction = 0·02 for 81 mg aspirin daily; P interaction = 0·03 for 325 mg aspirin daily). Folic acid supplementation was unrelated to BCC incidence (HR 0·85; 95% CI 0·57-1·27)., Conclusions: Neither aspirin nor folic acid treatment had a statistically significant effect on risk of BCC. Subgroup analysis suggested that chemopreventive effects of nonsteroidal anti-inflammatory drugs may be specific to those at high risk for BCC., (© 2018 British Association of Dermatologists.)

In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid (UFA) or natural reduced and methylated folates (mF) to which it is metabolized. In post hoc analyses, we measured mF (the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and UFA concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the prespecified, composite endpoint of high-risk findings (advanced or multiple adenomas) was positively associated with plasma mF ( P linear trend = 0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend ( P linear trend =0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper versus lower quartile participants ( P linear trend = 0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps. Cancer Prev Res; 10(8); 451-8. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Inflammation plays a major role in colon carcinogenesis. Endogenously produced specialized proresolving lipid mediators (SPMs) play a central role in inflammation and tissue homeostasis, and have been implicated in carcinogenesis. We studied the associations of plasma levels of two SPMs [lipoxin A 4 (LXA 4 ) and resolvin D1(RvD1)] with risk for recurrent adenoma. In this pilot study, we used data and biosamples from an adenoma chemoprevention study investigating the effects of aspirin and/or folic acid on the occurrence of colorectal adenomas. In the parent study, 1121 participants with a recent adenoma were randomized to study agents to be taken until the next surveillance colonoscopy about 3 years later. In this pilot study, LXA 4 and RvD1 from samples taken near the end of study treatment were measured in a randomly selected sub-set of 200 participants. Commercially available ELISA kits to assay the analytes were validated using a metabololipidomic LC-MS/MS assay. Poisson regression with a robust error variance was used to calculate risk ratios and 95% confidence intervals. Plasma LXA 4 and RvD1 were not associated with the risk of adenoma occurrence. LXA 4 at the end of study follow-up was 32% (P = 0.01) proportionately higher in women compared to men. A similar non-significant trend toward higher levels among women was observed for RvD1. Our preliminary findings provided no evidence that plasma LXA 4 or RvD1 are associated with reduced risk of colorectal adenoma occurrence, but suggest LXA 4 may differ among men and women. Future studies focusing on SPM's local effects and levels in the colon are needed., (© 2017 Wiley Periodicals, Inc.)

Background & Aims: Endoscopists do not routinely follow guidelines to survey individuals with low-risk adenomas (LRAs; 1-2 small tubular adenomas, < 1 cm) every 5-10 years for colorectal cancer; many recommend shorter surveillance intervals for these individuals. We aimed to identify the reasons that endoscopists recommend shorter surveillance intervals for some individuals with LRAs and determine whether timing affects outcomes at follow-up examinations., Methods: We collected data from 1560 individuals (45-75 years old) who participated in a prospective chemoprevention trial (of vitamin D and calcium) from 2004 through 2008. Participants in the trial had at least 1 adenoma, detected at their index colonoscopy, and were recommended to receive follow-up colonoscopy examinations at 3 or 5 years after adenoma identification, as recommended by the endoscopist. For this analysis we collected data from only participants with LRAs. These data included characteristics of participants and endoscopists and findings from index and follow-up colonoscopies. Primary endpoints were frequency of recommending shorter (3-year) vs longer (5-year) surveillance intervals, factors associated with these recommendations, and effect on outcome, determined at the follow-up colonoscopy., Results: A 3-year surveillance interval was recommended for 594 of the subjects (38.1%). Factors most significantly associated with recommendation of 3-year vs a 5-year surveillance interval included African American race (relative risk [RR] to white, 1.41; 95% confidence interval [CI], 1.14-1.75), Asian/Pacific Islander ethnicity (RR to white, 1.7; 95% CI, 1.22-2.43), detection of 2 adenomas at the index examination (RR vs 1 adenoma, 1.47; 95% CI, 1.27-1.71), more than 3 serrated polyps at the index examination (RR=2.16, 95% CI, 1.59-2.93), or index examination with fair or poor quality bowel preparation (RR vs excellent quality, 2.16; 95% CI, 1.66-2.83). Other factors that had a significant association with recommendation for a 3-year surveillance interval included family history of colorectal cancer and detection of 1-2 serrated polyps at the index examination. In comparisons of outcomes, we found no significant differences between the 3-year vs 5-year recommendation groups in proportions of subjects found to have 1 or more adenomas (38.8% vs 41.7% respectively; P = .27), advanced adenomas (7.7% vs 8.2%; P = .73) or clinically significant serrated polyps (10.0% vs 10.3%; P = .82) at the follow-up colonoscopy., Conclusions: Possibly influenced by patients' family history, race, quality of bowel preparation, or number or size of polyps, endoscopists frequently recommend 3-year surveillance intervals instead of guideline-recommended intervals of 5 years or longer for individuals with LRAs. However, at the follow-up colonoscopy, similar proportions of participants have 1 or more adenomas, advanced adenomas, or serrated polyps. These findings support the current guideline recommendations of performing follow-up examinations of individuals with LRAs at least 5 years after the index colonoscopy., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Importance: Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial., Objective: To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence., Design, Setting, and Participants: We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016., Interventions: Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither., Main Outcomes and Measures: The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ≥1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing., Results: Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D' = 0.98; r2 = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation., Conclusions and Relevance: Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype., Trial Registration: clinicaltrials.gov Identifier: NCT00153816.

APC/β-catenin pathway malfunction is a common and early event in colorectal carcinogenesis. To assess calcium and vitamin D effects on the APC/β-catenin pathway in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, nested within a larger randomized, double-blind, placebo-controlled, partial 2 × 2 factorial chemoprevention clinical trial of supplemental calcium (1200 mg daily) and vitamin D (1000 IU daily), alone and in combination versus placebo, we assessed APC, β-catenin, and E-cadherin expression in colon crypts in normal-appearing rectal mucosa biopsies from 104 participants at baseline and 1-yr follow up using standardized, automated immunohistochemistry and quantitative image analysis. For vitamin D versus no vitamin D, the ratio of APC expression to β-catenin expression in the upper 40% (differentiation zone) of crypts (APC/β-catenin score) increased by 28% (P = 0.02), for calcium versus no calcium it increased by 1% (P = 0.88), and for vitamin D + calcium versus calcium by 35% (P = 0.01). Total E-cadherin expression increased by 7% (P = 0.35) for vitamin D versus no vitamin D, 8% (P = 0.31) for calcium versus no calcium, and 12% (P = 0.21) for vitamin D + calcium versus calcium. These results support (i) that vitamin D, alone or in combination with calcium, may modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms; (ii) vitamin D as a potential chemopreventive agent against colorectal neoplasms; and (iii) the potential of APC, β-catenin, and E-cadherin expression as treatable, pre-neoplastic risk biomarkers for colorectal neoplasms. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)