Calcium Intake and Lung Cancer Risk: A Pooled Analysis of 12 Prospective Cohort Studies.

BACKGROUND: Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to the differences in intake amounts and contributing sources of calcium and smoking prevalence. OBJECTIVES: We investigated the associations of lung cancer risk with intake of calcium from foods and/or supplements and major calcium-rich foods in 12 studies. METHODS: Data from 12 prospective cohort studies conducted in the United States, Europe, and Asia were pooled and harmonized. We applied the DRI to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intake. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall HR (95% CI). RESULTS: Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 y. Overall, the dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98-1.18) for higher (>1.5 RDA) and 1.01 (0.95-1.07) for lower intake (<0.5 RDA) comparing with recommended intake (EAR to RDA). Milk and soy food intake were positively or inversely associated with lung cancer risk [HR (95% CI) = 1.07 (1.02-1.12) and 0.92 (0.84-1.00)], respectively. The positive association with milk intake was significant only in European and North American studies (P-interaction for region = 0.04). No significant association was observed for calcium supplements. CONCLUSIONS: In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

Coffee Consumption and C-Reactive Protein Levels: A Systematic Review and Meta-Analysis.

Coffee contains bioactive compounds with anti-inflammatory properties, and its consumption may reduce c-reactive protein (CRP) levels, a biomarker of chronic inflammation. A previous meta-analysis reported no overall association between blood CRP level and coffee consumption by modeling the coffee consumption in categories, with substantial heterogeneity. However, the coffee cup volume was not considered. We conducted a systematic review and dose-response meta-analysis investigating the association between coffee consumption and CRP levels reported in previous observational studies. A dose-response meta-analysis was conducted by mixed-effects meta-regression models using the volume of coffee consumed as metric. Eleven studies from three continents were identified using the PubMed database, totaling 61,047 participants. Three studies with the largest sample sizes observed a statistically significant association between coffee and CRP levels, which was inverse among European and United States (US) women and Japanese men (1.3%-5.5% decrease in CRP per 100 mL of coffee consumed) and positive among European men (2.2% increase). Other studies showed no statistically significant associations. When all studies were combined in the dose-response meta-analysis, no statistically significant associations were observed among all participants or when stratified by gender or geographic location, reflecting the conflicting associations reported in the included studies. Further studies are warranted to explore these inconsistent associations.

Food intake of folate, folic acid and other B vitamins with lung cancer risk in a low-income population in the Southeastern United States.

PURPOSE: We prospectively examined associations of lung cancer risk with food intake of B vitamins involved in one-carbon metabolism and the use of folic acid-containing supplements among a low-income population of black and white adults in the Southeastern US. METHODS: Within the Southern Community Cohort Study, we included 1064 incident lung cancer cases among 68,236 participants aged 40-79 years at study enrollment. Food intake and the use of folic acid-containing supplements were assessed using a validated food frequency questionnaire at study enrollment. Multivariate Cox regression was used to estimate hazards ratios (HRs) and the 95% confidence intervals (CIs). RESULTS: Folate and/or folic acid intake from food were not associated with lung cancer risk; HRs (95% CI) for highest compared with lowest quartile were 1.08 (0.91-1.29) for total dietary folate, 1.00 (0.84-1.19) for food folate, and 1.09 (0.91-1.30) for food folic acid, respectively. Similarly, no associations were observed after stratifying by sex, race and smoking status, except for a positive association with total dietary folate intake among black women (HR 1.46, 95% CI 1.04-2.05 for the highest quartile compared with the lowest quartile, P trend = 0.02). Neither the use of folic acid-containing supplements nor food intake of vitamin B6, vitamin B12 and riboflavin were associated with lung cancer risk. CONCLUSIONS: Our findings do not support a protective effect of folate or folic acid for lung cancer prevention in a low-income population of black and white adults in the Southeastern US. Our finding of a positive association with total dietary folate intake among black women needs to be interpreted with caution and replicated in other studies.

Phytol and its metabolites phytanic and pristanic acids for risk of cancer: current evidence and future directions.

This review summarizes the current evidence on the potential role of phytol, a microbial metabolite of chlorophyl A, and its metabolites, phytanic and pristanic acids, in carcinogenesis. Primary food sources in Western diets are the nut skin for phytol and lipids in dairy, beef and fish for its metabolites. Phytol and its metabolites gained interest as dietary compounds for cancer prevention because, as natural ligands of peroxisome proliferator-activated receptor-α and -γ and retinoid X receptor, phytol and its metabolites have provided some evidence in cell culture studies and limited evidence in animal models of anti-carcinogenic, anti-inflammatory and anti-metabolic-syndrome properties at physiological concentrations. However, there may be a narrow range of efficacy, because phytol and its metabolites at supra-physiological concentrations can cause in vitro cytotoxicity in non-cancer cells and can cause morbidity and mortality in animal models. In human studies, evidence for a role of phytol and its metabolites in cancer prevention is currently limited and inconclusive. In short, phytol and its metabolites are potential dietary compounds for cancer prevention, assuming the challenges in preventing cytotoxicity in non-cancer cells and animal models and understanding phytol metabolism can be mitigated.

Plasma selenoprotein P concentration and lung cancer risk: results from a case-control study nested within the Shanghai Men's Health Study.

Selenoprotein P (SELENOP) is a major selenoenzyme in plasma and linked to antioxidant properties and possibly to lung cancer; however, supporting evidence is limited. We investigated the association between pre-diagnostic plasma SELENOP concentration and lung cancer risk in a case-control study of 403 cases and 403 individually matched controls nested within the Shanghai Men's Health Study. SELENOP concentration in pre-diagnostic plasma samples was measured by a sandwich enzyme-linked immunosorbent assay. Cases were diagnosed with lung cancer between 2003 and 2010. Multivariate conditional logistic regression was used to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI) for studying the association between plasma SELENOP concentration and lung cancer risk. Cases had slightly lower plasma SELENOP concentration than controls (4.3 ± 1.2 versus 4.4 ± 1.1 mg/l, P difference = 0.09). However, the multivariate analysis showed no association between plasma SELENOP concentration and lung cancer risk among all participants (OR = 1.08, 95% CI = 0.54-2.14 for quartile 4 versus quartile 1), or by smoking status or tumor aggressiveness. In contrast, although the number of cases was limited, plasma SELENOP concentration was positively associated with lung adenocarcinoma risk (OR = 5.38, 95% CI = 1.89-15.35 for tertile 3 versus tertile 1), but not with squamous cell lung carcinoma (OR = 1.69, 95% CI = 0.43-6.70). Our study of adult men living in selenium non-deficient areas in China provides little support for the inverse association between pre-diagnostic plasma SELENOP concentration and lung cancer risk. Our finding of a positive association with risk of lung adenocarcinoma needs to be interpreted with caution.

Prediagnostic Calcium Intake and Lung Cancer Survival: A Pooled Analysis of 12 Cohort Studies.

Background: Lung cancer is the leading cause of cancer death. Little is known about whether prediagnostic nutritional factors may affect survival. We examined the associations of prediagnostic calcium intake from foods and/or supplements with lung cancer survival.Methods: The present analysis included 23,882 incident, primary lung cancer patients from 12 prospective cohort studies. Dietary calcium intake was assessed using food-frequency questionnaires at baseline in each cohort and standardized to caloric intake of 2,000 kcal/d for women and 2,500 kcal/d for men. Stratified, multivariable-adjusted Cox regression was applied to compute hazard ratios (HR) and 95% confidence intervals (CI).Results: The 5-year survival rates were 56%, 21%, and 5.7% for localized, regional, and distant stage lung cancer, respectively. Low prediagnostic dietary calcium intake (<500-600 mg/d, less than half of the recommendation) was associated with a small increase in risk of death compared with recommended calcium intakes (800-1,200 mg/d); HR (95% CI) was 1.07 (1.01-1.13) after adjusting for age, stage, histology, grade, smoking status, pack-years, and other potential prognostic factors. The association between low calcium intake and higher lung cancer mortality was evident primarily among localized/regional stage patients, with HR (95% CI) of 1.15 (1.04-1.27). No association was found for supplemental calcium with survival in the multivariable-adjusted model.Conclusions: This large pooled analysis is the first, to our knowledge, to indicate that low prediagnostic dietary calcium intake may be associated with poorer survival among early-stage lung cancer patients.Impact: This multinational prospective study linked low calcium intake to lung cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(7); 1060-70. ©2017 AACR.

Plasma folate concentrations and colorectal cancer risk: a case-control study nested within the Shanghai Men's Health Study.

Previous epidemiological studies of circulating folate concentration and colorectal cancer have reported inconsistent results. We evaluated associations of prediagnostic plasma folate concentration with colorectal cancer risk in a case-control study nested within the Shanghai Men's Health Study (2002-2010). Included herein are 288 cases who were diagnosed with incident colorectal cancer and 575 controls who were individually matched to cases on baseline characteristics. Folate concentrations in plasma were measured by microbiological assay. Multivariate conditional logistic regression was used to assess associations of plasma folate concentrations with colorectal cancer risk. Plasma folate was nonsignificantly but positively associated with colorectal cancer risk. Odds ratios (OR) and 95% confidence intervals (CI) were 1.38 (0.95-2.02) for the middle tertile of plasma folate concentrations and 1.33 (0.90-1.98) for the highest compared to the lowest tertile. The positive association reached statistical significance for the highest tertile of folate concentrations for men with late-stage colorectal cancer (OR = 2.66; 95% CI = 1.03-6.86) and for the middle tertile for cases diagnosed within the first 4 years after blood collection (OR = 1.72; 95% CI = 1.02-2.92) and for men in the high BMI group (OR = 1.88; 95% CI = 1.14-3.11). In our study population, where folic acid fortification of the food supply and vitamin supplement use are uncommon, plasma folate concentration was positively associated with colorectal cancer risk among men who may have had preneoplastic lesions. These findings need to be confirmed in studies with specific assessment of preneoplastic lesions and repeated measurements of folate level over time.

Calcium intake and lung cancer risk among female nonsmokers: a report from the Shanghai Women's Health Study.

BACKGROUND: Calcium has been implicated in carcinogenesis and linked to the risk of several cancers in epidemiologic studies; however, few studies have investigated the association of calcium intake with lung cancer risk, particularly among nonsmokers. METHODS: We evaluated the association of intakes of calcium and related minerals, assessed through a food frequency questionnaire, with lung cancer risk among 71,267 female nonsmokers who were cancer free at baseline in the Shanghai Women's Health Study, a population-based, prospective cohort study. Multivariate Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During follow-up through December 2009 (median follow-up time: 11.2 years), 428 incident lung cancer cases accrued. The median intakes of dietary calcium, magnesium, and phosphorus were 441, 266, and 935 mg/d, respectively. Intakes of calcium, phosphorus, and the calcium-to-magnesium (Ca:Mg) ratio were inversely associated with lung cancer risk. The corresponding HRs (95% CIs) for the highest compared with the lowest quartile were 0.66 (0.48, 0.91) for calcium, 0.55 (0.36, 0.85) for phosphorus, and 0.62 (0.47, 0.82) for the Ca:Mg ratio. No association was observed for dietary magnesium intake or the use of calcium- or vitamin D-containing supplements. CONCLUSIONS AND IMPACT: Our study provides some of the first evidence suggesting a possible role for increasing dietary calcium intake in lung cancer prevention among female nonsmokers, especially in populations with relatively low calcium intake.

Selenium, selenoenzymes, oxidative stress and risk of neoplastic progression from Barrett's esophagus: results from biomarkers and genetic variants.

Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31-32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12-0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation.

Genetic variation in GPX1 is associated with GPX1 activity in a comprehensive analysis of genetic variations in selenoenzyme genes and their activity and oxidative stress in humans.

Previous studies suggest some effects of selenium on risk of several chronic diseases, which may be mediated through a small number of selenoenzymes with antioxidant properties. In this cross-sectional analysis of 195 participants from the Seattle Barrett's Esophagus Study who were free of esophageal cancer at the time of blood draw, we examined whether the number of the minor alleles in 26 tagging single nucleotide polymorphisms (SNP) of five selenoenzyme genes [i.e., glutathione peroxidase 1-4 (GPX1-4) and selenoprotein P (SEPP1)] was associated with activity of GPX1 in white blood cells and GPX3 in plasma, and concentrations of SEPP1 and markers of oxidative stress [malondialdehyde (MDA) and protein carbonyl content] in plasma. At the gene level, associations were observed between overall variation in GPX1 and GPX1 activity (P = 0.02) as well as between overall variation in GPX2 and SEPP1 concentrations (P = 0.03). By individual SNP, two variants in GPX1 (rs8179164 and rs1987628) showed a suggestive association with GPX1 activity (P = 0.10 and 0.08, respectively) and two GPX2 variants (rs4902346 and rs2071566) were associated with SEPP1 concentration (P = 0.004 and 0.002, respectively). Furthermore, two SNP in the SEPP1 gene (rs230813 and rs230819) were associated with MDA concentrations (P = 0.03 and 0.02, respectively). Overall, our study supports the hypothesis that common genetic variants in selenoenzymes affect their activity.

Serum selenium, genetic variation in selenoenzymes, and risk of colorectal cancer: primary analysis from the Women's Health Initiative Observational Study and meta-analysis.

BACKGROUND: Selenium may prevent colorectal cancer. However, several previous studies are small and few investigated the association between selenium and colorectal cancer among women whose selenium metabolism may differ from men. Furthermore, genetic variants in selenoenzymes may be associated with colorectal cancer risk. METHODS: This nested case-control study investigated whether serum selenium concentration and genetic variants in five selenoenzymes (glutathione peroxidase 1-4 and selenoprotein P) were associated with colorectal cancer risk in 804 colorectal cancer cases and 805 matched controls from the Women's Health Initiative (WHI) Observational Study. A meta-analysis was conducted to compare the WHI result with previous studies including 12 observational studies and two clinical trials on selenium. RESULTS: Within the WHI, selenium concentrations were relatively high (mean = 135.6 µg/L) and were not associated with colorectal cancer risk (P(trend) = 0.10); the adjusted OR comparing the fifth with first quintile was 1.26 (95% CI, 0.91-1.73). Moreover, genetic variants in selenoenzymes were not significantly associated with colorectal cancer risk. Consistent with the finding in WHI, our meta-analysis showed no association between selenium and colorectal tumor risk in women (OR = 0.97; 95% CI, 0.79-1.18) comparing the highest quantile with the lowest); however, in men, there was a significant inverse association (OR = 0.68; 95% CI, 0.57-0.82) (P = 0.01). CONCLUSION: Consistent with previous studies, we observed no protective effect of selenium on colorectal cancer among women. IMPACT: Our analyses suggest that a population with relatively high selenium concentrations, especially women, would not benefit from increasing selenium intake.

Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue.

BACKGROUND: Low serum selenium concentration has been associated with increased risk of prostate cancer. A possible mechanism is through the antioxidant activity of selenoenzymes. However, the effect of selenium intake on selenoenzymes at target tissues is not well established. Hence, we investigated the correlation between serum and prostate tissue selenium concentrations and prostate tissue activity of glutathione peroxidase (GPX), a major selenoenzyme with antioxidant properties. METHODS: In an ongoing study investigating gene expression in prostate tissue, we measured serum selenium concentration in 98 men using atomic absorption spectrometry. Of these men, we selected 12 men with the highest and 12 men with the lowest serum selenium concentrations and measured selenium concentration and GPX activity in fresh frozen prostate tissue using the cyclic neutron activation analysis and a direct spectrophotometric procedure, respectively. RESULTS: The mean serum selenium concentrations among low and high selenium groups were 123.7 +/- 5.9 and 196.7 +/- 16.6 microg/L (P < 0.0001), respectively. The corresponding mean prostate tissue selenium concentrations were 1.39 +/- 0.28 and 1.65 +/- 0.42 microg/g (P = 0.08), resulting in a positive correlation between serum and prostate tissue selenium concentrations (r = 0.56, P = 0.02). The mean prostate tissue GPX activity was non-significantly greater in the low serum selenium group (32.2 +/- 8.4 U/g protein) than in the high serum selenium group (29.6 +/- 5.9 U/g protein) (P = 0.39) and it was not correlated with serum or prostate tissue selenium concentrations (r = -0.22, P = -0.37 for serum and r = -0.33, P = 0.18 for prostate tissue). CONCLUSION: Serum and prostate tissue selenium concentrations were moderately correlated. In this population with relatively high selenium concentration, neither prostate tissue nor serum selenium concentrations were associated with prostate tissue GPX activity.

Selenium and the prevention of prostate and colorectal cancer.

Prostate and colorectal cancers are among the most common cancers and identifying modifiable risk factors are important steps to reduce the burden of these severe diseases. Results from several but mostly small observational studies as well as the secondary analysis of an intervention trial provide support for a chemopreventive effect of selenium on prostate and colorectal cancers. Results suggest effect modification by gender and smoking, but this interpretation is limited by the statistical power of previous studies. Several cancer preventive mechanisms have been described and it is likely that selenium acts through multiple pathways. In particular, the anti-oxidative and anti-inflammatory effects mediated through activity of selenoenzymes are discussed, given the relevance of oxidative stress and inflammation in these cancers. Genetic variation in selenoenzymes may modify the potential chemopreventive effect of selenium and need to be further investigated. Additional large observational studies using biomarkers of selenium intake and intervention trials, such as the Selenium and Vitamin E Cancer Prevention Trial, will be important to further evaluate the potential chemopreventive effect of selenium. Furthermore, characterization of functional effects of polymorphisms in selenoenzymes is needed.