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

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

Characterization of additive gene-environment interactions for colorectal cancer risk.

BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

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

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

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

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

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

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

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

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

Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common, inherited vitamin D-binding protein isoforms.

Lower prediagnostic circulating 25-hydroxyvitamin D (25[OH]D)-considered the best marker of total vitamin D exposure-is associated with higher mortality risk among colorectal cancer (CRC) patients. However, it is unknown whether this association differs by the vitamin D-binding protein (GC) isoform Gc2 (encoded by GC rs4588*C>A, Thr436Lys), which may substantially affect vitamin D metabolism and modify associations of 25(OH)D with colorectal neoplasm risk. Prediagnostic 25(OH)D-mortality associations according to Gc2 isoform were estimated using multivariable Cox proportional hazards regression among 1281 CRC cases (635 deaths, 483 from CRC) from two large prospective cohorts conducted in the United States (Cancer Prevention Study-II) and Europe (European Prospective Investigation into Cancer and Nutrition). 25(OH)D measurements were calibrated to a single assay, season standardized, and categorized using Institute of Medicine recommendations (deficient [<30], insufficient [30 - <50], sufficient [≥50 nmol/L]). In the pooled analysis, multivariable-adjusted hazard ratios (HRs) for CRC-specific mortality associated with deficient relative to sufficient 25(OH)D concentrations were 2.24 (95% CI 1.44-3.49) among cases with the Gc2 isoform, and 0.94 (95% CI 0.68-1.22) among cases without Gc2 (Pinteraction = .0002). The corresponding HRs for all-cause mortality were 1.80 (95% CI 1.24-2.60) among those with Gc2, and 1.12 (95% CI 0.84-1.51) among those without Gc2 (Pinteraction = .004). Our findings suggest that the association of prediagnostic vitamin D status with mortality among CRC patients may differ by functional GC isoforms, and patients who inherit the Gc2 isoform (GC rs4588*A) may particularly benefit from higher circulating 25(OH)D for improved CRC prognosis.

Association between grains, gluten and the risk of colorectal cancer in the Cancer Prevention Study-II Nutrition Cohort.

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

Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial.

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFß1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFß1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFß1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFß1 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, TGFß1 alone, and TGFα relative to TGFß1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.

Associations of Calcium, Vitamin D, and Dairy Product Intakes with Colorectal Cancer Risk among Older Women: The Iowa Women's Health Study.

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

Associations of calcium and dairy product intakes with all-cause, all-cancer, colorectal cancer and CHD mortality among older women in the Iowa Women's Health Study.

Ca and dairy product intakes may be inversely associated with all-cause and cause-specific mortality, and non-Ca components of dairy products, such as insulin-like growth factor-1, may be independently associated with mortality. We investigated associations of Ca and dairy product intakes with all-cause, all-cancer, colorectal cancer (CRC) and CHD mortality among 35 221 55- to 69-year-old women in the prospective Iowa Women's Health Study, who were cancer-free in 1986. We assessed diet using a Willett FFQ, and associations using multivariable Cox proportional hazards regression. We estimated residuals from linear regression models of dairy products with dietary Ca to investigate total and specific dairy products independent of their Ca content. Through 2012, 18 687 participants died, including 4665 from cancer (including 574 from CRC) and 3603 from CHD. For those in the highest relative to the lowest quintiles of intake, the multivariable-adjusted hazard ratios (HR) and 95 % CI for total Ca (dietary plus supplemental) were 0·88 (0·83, 0·93; P trend=0·001) for all-cause mortality, 0·91 (0·81, 1·02; P trend=0·34) for all-cancer mortality, 0·60 (0·43, 0·83; P trend=0·002) for CRC mortality and 0·73 (0·64, 0·83; P trend <0·0001) for CHD mortality. The corresponding HR for associations of whole milk, whole milk residuals, and low-/non-fat milk residuals with all-cause mortality were 1·20 (95 % CI 1·13, 1·27), 1·20 (95 % CI 1·13, 1·28) and 0·91 (95 % CI 0·86, 0·96), respectively. These results suggest that Ca may be associated with lower risk of all-cause, CRC and CHD mortality, and that non-Ca components of milk may be independently associated with mortality.

Circulating γ-Tocopherol Concentrations Are Inversely Associated with Antioxidant Exposures and Directly Associated with Systemic Oxidative Stress and Inflammation in Adults.

Background: Although α- and γ-tocopherol are co-consumed antioxidants, circulating γ-tocopherol concentrations were paradoxically found to be inversely associated with total vitamin E intake and circulating α-tocopherol concentrations. There are limited data on this apparent paradox or on determinants of circulating γ-tocopherol concentrations. Objective: To help clarify possible determinants of circulating γ-tocopherol concentrations, we investigated associations of circulating γ-tocopherol concentrations with various dietary and lifestyle factors and biomarkers of oxidative stress and inflammation. Methods: We pooled cross-sectional data from 2 outpatient, adult, elective colonoscopy populations (pooled n = 419) on whom extensive dietary, lifestyle, and medical information was collected, and the following plasma concentrations were measured: α- and γ-tocopherol (via HPLC), F2-isoprostanes (FiPs; via gas chromatography-mass spectrometry), and high-sensitivity C-reactive protein (hsCRP; via latex-enhanced immunonephelometry). Multivariable general linear models were used to assess mean γ-tocopherol differences across quantiles of plasma antioxidant micronutrients, FiPs, and hsCRP; an oxidative balance score [OBS; a composite of anti- and pro-oxidant dietary and lifestyle exposures (a higher score indicates higher antioxidant relative to pro-oxidant exposures)]; and multiple dietary and lifestyle factors. Results: Adjusted for serum total cholesterol, mean γ-tocopherol concentrations among those in the highest relative to the lowest tertiles of circulating α-tocopherol and ß-carotene, the OBS, and total calcium and dietary fiber intakes were 31.0% (P < 0.0001), 29.0% (P < 0.0001), 27.6% (P = 0.0001), 29.7% (P < 0.0001), and 18.6% (P = 0.008) lower, respectively. For those in the highest relative to the lowest tertiles of circulating FiPs and hsCRP, mean γ-tocopherol concentrations were 50% (P < 0.0001) and 39.0% (P < 0.0001) higher, respectively. Conclusions: These findings support the conclusion that circulating γ-tocopherol concentrations are inversely associated with antioxidant exposures and directly associated with systemic oxidative stress and inflammation in adults. Additional research on possible mechanisms underlying these findings and on whether circulating γ-tocopherol may serve as a biomarker of oxidative stress, inflammation, or both is needed.

Associations of evolutionary-concordance diet, Mediterranean diet and evolutionary-concordance lifestyle pattern scores with all-cause and cause-specific mortality.

Various individual diet and lifestyle factors are associated with mortality. Investigating these factors collectively may help clarify whether dietary and lifestyle patterns contribute to life expectancy. We investigated the association of previously described evolutionary-concordance and Mediterranean diet pattern scores and a novel evolutionary-concordance lifestyle pattern score with all-cause and cause-specific mortality in the prospective Iowa Women's Health Study (1986-2012). We created the diet pattern scores from Willett FFQ responses, and the lifestyle pattern score from self-reported physical activity, BMI and smoking status, and assessed their associations with mortality, using multivariable Cox proportional hazards regression. Of the 35 221 55- to 69-year-old cancer-free women at baseline, 18 687 died during follow-up. The adjusted hazard ratios (HR) and 95 % CI for all-cause, all CVD, and all-cancer mortality among participants in the highest relative to the lowest quintile of the evolutionary-concordance lifestyle score were, respectively, 0·52 (95 % CI 0·50, 0·55), 0·53 (95 % CI 0·49, 0·57) and 0·51 (95 % CI 0·46, 0·57). The corresponding findings for the Mediterranean diet score were HR 0·85 (95 % CI 0·82, 0·90), 0·83 (95 % CI 0·76, 0·90) and 0·93 (95 % CI 0·84, 1·03), and for the evolutionary-concordance diet score they were close to null and not statistically significant. The lowest estimated risk was among those in the highest joint quintile of the lifestyle score and either diet score (both Pinteraction <0·01). Our findings suggest that (1) a more Mediterranean-like diet pattern and (2) a more evolutionary-concordant lifestyle pattern, alone and in interaction with a more evolutionary-concordant or Mediterranean diet pattern, may be inversely associated with mortality.

Circulating insulin-like growth factor-related biomarkers: Correlates and responses to calcium supplementation in colorectal adenoma patients.

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

Associations of Calcium and Dairy Products with All-Cause and Cause-Specific Mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Prospective Cohort Study.

Associations of calcium and dairy product intakes with cardiovascular disease risk and cancer mortality are controversial. We investigated associations of calcium and dairy product intakes with mortality in the prospective REasons for Geographic and Racial Differences in Stroke study (n = 30,239). Of 2,966 total deaths, 32.3% were from CVD and 28.8% from cancer. For those in the upper relative to the lowest quintile of intakes, from Cox proportional hazards regression models, the multivariable-adjusted hazard ratios (HRs) for all-cause mortality were 1.13 (95% confidence intervals [CI] 0.95-1.35; P-trend 0.004) for whole milk, and 0.75 (CI 0.61-0.93; P-trend 0.001) for nonfat milk; for CVD mortality the corresponding HRs were 0.80 (CI 0.55-1.16; P-trend 0.80) and 0.72 (CI 0.49-1.05; P-trend 0.06); and for cancer mortality they were 1.56 (CI 1.17-2.08; P-trend 0.006) and 0.89 (CI 0.62-1.28; P-trend 0.86). Calcium (total, dietary, supplemental) and total dairy product intakes were not associated with all-cause, cardiovascular, or cancer mortality. These results suggest that whole milk consumption may be directly associated with cancer mortality; non-fat milk consumption may be inversely associated with all-cause and cardiovascular- and cancer-specific mortality; and calcium intake independent of milk product intakes may not be associated with mortality.

Associations of Calcium and Milk Product Intakes with Incident, Sporadic Colorectal Adenomas.

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

Oral Microbiome and Subsequent Risk of Head and Neck Squamous Cell Cancer.

Importance: The oral microbiota may be involved in development of head and neck squamous cell cancer (HNSCC), yet current evidence is largely limited to bacterial 16S amplicon sequencing or small retrospective case-control studies. Objective: To test whether oral bacterial and fungal microbiomes are associated with subsequent risk of HNSCC development. Design, Setting, and Participants: Prospective nested case-control study among participants providing oral samples in 3 epidemiological cohorts, the American Cancer Society Cancer Prevention Study II Nutrition Cohort, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and the Southern Community Cohort Study. Two hundred thirty-six patients who prospectively developed HNSCC were identified during a mean (SD) of 5.1 (3.6) years of follow-up. Control participants who remained HNSCC free were selected by 2:1 frequency matching on cohort, age, sex, race and ethnicity, and time since oral sample collection. Data analysis was conducted in 2023. Exposures: Characterization of the oral bacterial microbiome using whole-genome shotgun sequencing and the oral fungal microbiome using internal transcribed spacer sequencing. Association of bacterial and fungal taxa with HNSCC was assessed by analysis of compositions of microbiomes with bias correction. Association with red and orange oral pathogen complexes was tested by logistic regression. A microbial risk score for HNSCC risk was calculated from risk-associated microbiota. Main Outcomes and Measures: The primary outcome was HNSCC incidence. Results: The study included 236 HNSCC case participants with a mean (SD) age of 60.9 (9.5) years and 24.6% women during a mean of 5.1 (3.6) years of follow-up, and 485 matched control participants. Overall microbiome diversity at baseline was not related to subsequent HNSCC risk; however 13 oral bacterial species were found to be differentially associated with development of HNSCC. The species included the newly identified Prevotella salivae, Streptococcus sanguinis, and Leptotrichia species, as well as several species belonging to beta and gamma Proteobacteria. The red/orange periodontal pathogen complex was moderately associated with HNSCC risk (odds ratio, 1.06 per 1 SD; 95% CI, 1.00-1.12). A 1-SD increase in microbial risk score (created based on 22 bacteria) was associated with a 50% increase in HNSCC risk (multivariate odds ratio, 1.50; 95% CI, 1.21-1.85). No fungal taxa associated with HNSCC risk were identified. Conclusions and Relevance: This case-control study yielded compelling evidence that oral bacteria are a risk factor for HNSCC development. The identified bacteria and bacterial complexes hold promise, along with other risk factors, to identify high-risk individuals for personalized prevention of HNSCC.

Altered salivary microbiota associated with high-sugar beverage consumption.

The human oral microbiome may alter oral and systemic disease risk. Consuming high sugar content beverages (HSB) can lead to caries development by altering the microbial composition in dental plaque, but little is known regarding HSB-specific oral microbial alterations. Therefore, we conducted a large, population-based study to examine associations of HSB intake with oral microbiome diversity and composition. Using mouthwash samples of 989 individuals in two nationwide U.S. cohorts, bacterial 16S rRNA genes were amplified, sequenced, and assigned to bacterial taxa. HSB intake was quantified from food frequency questionnaires as low (< 1 serving/week), medium (1-3 servings/week), or high (> 3 servings/week). We assessed overall bacterial diversity and presence of specific taxa with respect to HSB intake in each cohort separately and combined in a meta-analysis. Consistently in the two cohorts, we found lower species richness in high HSB consumers (> 3 cans/week) (p = 0.027), and that overall bacterial community profiles differed from those of non-consumers (PERMANOVA p = 0.040). Specifically, presence of a network of commensal bacteria (Lachnospiraceae, Peptostreptococcaceae, and Alloprevotella rava) was less common in high compared to non-consumers, as were other species including Campylobacter showae, Prevotella oulorum, and Mycoplasma faucium. Presence of acidogenic bacteria Bifodobacteriaceae and Lactobacillus rhamnosus was more common in high consumers. Abundance of Fusobacteriales and its genus Leptotrichia, Lachnoanaerobaculum sp., and Campylobacter were lower with higher HSB consumption, and their abundances were correlated. No significant interaction was found for these associations with diabetic status or with microbial markers for caries (S. mutans) and periodontitis (P. gingivalis). Our results suggest that soft drink intake may alter the salivary microbiota, with consistent results across two independent cohorts. The observed perturbations of overrepresented acidogenic bacteria and underrepresented commensal bacteria in high HSB consumers may have implications for oral and systemic disease risk.

Calcium intake and genetic variants in the calcium sensing receptor in relation to colorectal cancer mortality: an international consortium study of 18,952 patients.

Background: Research on calcium intake as well as variants in the calcium sensor receptor (CaSR) gene and their interaction in relation to CRC survival is still limited. Methods: Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary (n = 13.085), supplemental (n = 11,837), total calcium intake (n = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene (n = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed. Results: During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene. Conclusion: Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene.

Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing.

BACKGROUND: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer. OBJECTIVE: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing. DESIGN: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-ß, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors. RESULTS: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways. CONCLUSIONS: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.