Is high vitamin B12 status a cause of lung cancer?

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

Diurnal variation of metabolites in three individual participants.

The circadian system influences virtually all biological functions. Understanding the impact of circadian variation on metabolism may provide insight into mechanisms of circadian-associated disorders and guide the implementation of chrono-therapy. Previous research has reported circadian variation in 7-20% of metabolites in human blood. In this study, untargeted metabolomics profiles were measured using blood of two healthy men and one healthy woman, collected every 2 h for up to 48 h under carefully controlled conditions. The pattern of variation of each metabolite over time was examined on each participant separately, using both one- and two-order harmonic models. A total of 100 of 663 metabolites, representing all metabolite categories, showed diurnal rhythmic concentrations that exceeded the Bonferroni threshold (P < 2.5 × 10-5). Overall, peak times of many metabolites were clustered during the afternoon-midnight, including the majority of amino acids, all peptides, all lysolipids and all phospholipids, whereas the majority of steroids peaked in the morning. We observed substantial inter-individual variation for both peak times and amplitudes in these three subjects. In conclusion, at least 15% of blood metabolites, representing a broad group of biological pathways, exhibit diurnal variation in three participants. The average peak times of most of these metabolites are clustered in morning or afternoon-midnight. Further work is needed to validate and extend this work in more individuals.

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Coffee consumption and incidence of lung cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Coffee drinkers had a higher risk of lung cancer in some previous studies, but as heavy coffee drinkers tend to also be cigarette smokers, such findings could be confounded. Therefore, we examined this association in the nearly half a million participants of the US NIH-AARP Diet and Health Study. METHODS: Typical coffee intake and smoking history were queried at baseline. During 4 155 256 person-years of follow-up, more than 9000 incident lung cancer cases occurred. We used Cox proportional hazards regression to estimate hazard ratios (HRs)and 95% confidence intervals for coffee intake and subsequent incidence of lung cancer. We also comprehensively adjusted for tobacco smoking and examined associations by detailed strata of tobacco use. RESULTS: Coffee drinkers were far more likely to smoke than non-drinkers. Although coffee drinking was associated with lung cancer in age- and sex- adjusted models (HR for ≥ 6 cups/day compared with none: 4.56, 4.08-5.10), this association was substantially attenuated after adjusting for smoking (HR: 1.27, 1.14-1.42). Similar findings were observed for each different histological type of lung cancer, and for participants drinking predominantly caffeinated or decaffeinated coffee. Little evidence for an association was observed in our stratified analyses, either within never smokers or in most categories of tobacco use. CONCLUSIONS: Coffee drinking was positively associated with lung cancer in our study, although the association was substantially attenuated after adjustment for tobacco smoking. As our adjustment for lifetime tobacco use was imperfect, it is likely that the remaining association is due to residual confounding by smoking, although other explanations are possible.

Caffeine, coffee, and tea intake and urinary estrogens and estrogen metabolites in premenopausal women.

BACKGROUND: Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. METHODS: High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. RESULTS: Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; Ptrend = 0.01) and 16-epiestriol (13% difference; Ptrend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (Ptrend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; Ptrend = 0.001) and 2-hydroxyestrone (52% difference; Ptrend = 0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1-3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; Ptrend = 0.01) and 17-epiestriol (48% difference; Ptrend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend = 0.01). CONCLUSION: Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. IMPACT: Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism.

Integrative cancer epidemiology--the next generation.

We outline an integrative approach to extend the boundaries of molecular cancer epidemiology by integrating modern and rapidly evolving "omics" technologies into state-of-the-art molecular epidemiology. In this way, one can comprehensively explore the mechanistic underpinnings of epidemiologic observations in cancer risk and outcome. We highlight the exciting opportunities to collaborate across large observational studies and to forge new interdisciplinary collaborative ventures.