Risk Factors for Lung Cancer and for Intervention Effects in CARET, the Beta-Carotene and Retinol Efficacy Trial

Omenn, Gilbert S.; Goodman, Gary E.; Thornquist, Mark; Balmes, John R.; Cullen, Mark R.; Glass, Andrew G.; Keogh, James P.; Meyskens, Frank L.; Valanis, Barbara; Williams, J. H.; Barnhart, Scott; Cherniack, Martin G.; Brodkin, Carl A.; Hammar, Samuel P.

doi:10.1093/jnci/88.21.1550

Cited by 1,120 publications

(566 citation statements)

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“…In contrast to the results of many observational studies and the current meta‐analysis, two large randomized controlled trials (RCT's), the ATBC and CARET, showed an increased risk of lung cancer with high‐dose supplemental β ‐carotene among smokers 14, 15, 16. The increased risk at high doses may be related to the prooxidant activity of β ‐carotene when administered as a supplement in high doses (5–10 times greater than normal dietary intake) to heavy smokers 6, 45, 46.…”

Section: Discussioncontrasting

confidence: 91%

“…By contrast, two large randomized double‐blind placebo‐controlled trials, the alpha‐tocopherol‐ β ‐carotene (ATBC) and the β ‐carotene and Retinol Efficacy Trial (CARET) showed an increased risk of lung cancer among high‐risk people supplemented with high doses of β ‐carotene and/or α ‐tocopherol 13, 14, 15, 16.…”

Section: Introductionmentioning

confidence: 98%

“…As part of the WCRF/AICR Continuous Update Project (CUP), we conducted an updated systematic review and meta‐analysis of cohort studies with the aim to clarify the relationship of blood carotenoids and lung cancer risk. Retinol was also included in this review because of the conflicting results of randomized controlled trials 13, 14, 15, 16.…”

Section: Introductionmentioning

confidence: 99%

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Blood concentrations of carotenoids and retinol and lung cancer risk: an update of the WCRF–AICR systematic review of published prospective studies

et al. 2016

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Carotenoids and retinol are considered biomarkers of fruits and vegetables intake, and are of much interest because of their anti‐inflammatory and antioxidant properties; however, there is inconsistent evidence regarding their protective effects against lung cancer. We conducted a meta‐analysis of prospective studies of blood concentrations of carotenoids and retinol, and lung cancer risk. We identified relevant prospective studies published up to December 2014 by searching the PubMed and several other databases. We calculated summary estimates of lung cancer risk for the highest compared with lowest carotenoid and retinol concentrations and dose–response meta‐analyses using random effects models. We used fractional polynomial models to assess potential nonlinear relationships. Seventeen prospective studies (18 publications) including 3603 cases and 458,434 participants were included in the meta‐analysis. Blood concentrations of α‐carotene, β‐carotene, total carotenoids, and retinol were significantly inversely associated with lung cancer risk or mortality. The summary relative risk were 0.66 (95% confidence interval [CI]: 0.55–0.80) per 5 μg/100 mL of α‐carotene (studies [n] = 5), 0.84 (95% CI: 0.76–0.94) per 20 μg/100 mL of β‐carotene (n = 9), 0.66 (95% CI: 0.54–0.81) per 100 μg/100 mL of total carotenoids (n = 4), and 0.81 (95% CI: 0.73–0.90) per 70 μg/100 mL of retinol (n = 8). In stratified analysis by sex, the significant inverse associations for β‐carotene and retinol were observed only in men and not in women. Nonlinear associations were observed for β‐carotene, β‐cryptoxanthin, and lycopene, with stronger associations observed at lower concentrations. There were not enough data to conduct stratified analyses by smoking. In conclusion, higher blood concentrations of several carotenoids and retinol are associated with reduced lung cancer risk. Further studies in never and former smokers are needed to rule out confounding by smoking.

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Section: Discussioncontrasting

confidence: 91%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Blood concentrations of carotenoids and retinol and lung cancer risk: an update of the WCRF–AICR systematic review of published prospective studies

et al. 2016

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“…As a result, the genetic make-up of participants in supplementation trails may influence the outcome of such trials. Therefore genetics may be a factor, along with differences in environmental stress, lifestyle behaviour and Se intake, that contributes to differences in study populations that could explain why micronutrient supplementation trials, including those with Se, have been disappointing or contradictory (see, for example (4)(5)(6)(7)(8)(9) ). The identification of genetic differences in micronutrient metabolism may useful in improving the design of future supplementation trials.…”

Section: Future Perspectivesmentioning

confidence: 99%

Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar

Hesketh

Méplan

2011

Proc. Nutr. Soc.

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Micronutrients are essential for optimal human health. However, in some cases, raising intake by supplementation has not proven to be beneficial and there is even some evidence that supplementation may increase disease risk, highlighting the importance of assessing the functional status of micronutrients. Techniques such as gene microarrays and single-nucleotide polymorphism analysis have the potential to examine effects of micronutrient intake on patterns of gene expression and inter-individual variation in micronutrient metabolism. Recent genomic research related to selenium (Se) provides examples illustrating how studies of functional single-nucleotide polymorphism and gene expression patterns can reveal novel biomarkers of micronutrient function. Both in vitro and in vivo experiments show that there are functionally relevant polymorphisms in genes encoding glutathione peroxidases 1, 3 and 4, selenoprotein P, selenoprotein S and the 15 kDa selenoprotein. Disease association studies investigating these gene variants have so far been relatively small but an association of a polymorphism in the selenoprotein S gene with colorectal cancer risk has been replicated in two distinct populations. Future disease association studies should examine effects of multiple variants in combination with nutritional status. Gene microarray studies indicate that changes in Se intake alter expression of components of inflammatory, stress response and translation pathways. Our hypothesis is that Se intake and genetic factors have linked effects on stress response, inflammation and apoptotic pathways. Combining such data in a systems biology approach has the potential to identify both biomarkers of micronutrients status and sub-group populations at particular risk.

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“…However, results of antioxidant supplementation trials have largely been disappointing, demonstrating little effect of Se and vitamins E and C on gastric cancer [180] and no effect of vitamin E and β-carotene on the prevention of heart disease [181]. Some randomized, controlled trials have actually displayed adverse effects of supplementation with antioxidants such as β-carotene and vitamins E or A on lung cancer and heart disease [118,182,183], demonstrating a need for caution. In other trials, the results have been mixed: Se supplementation correlated with an increased risk of some cancers and a reduced risk of others [173].…”

Section: History Of Clinical Trials Of Antioxidants In Other Diseasesmentioning

confidence: 99%

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Cantin

White

Cross

et al. 2007

Free Radical Biology and Medicine

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Although great strides are being made in the care of individuals with cystic fibrosis (CF), this condition remains the most common fatal hereditary disease in North America. Numerous links exist between progression of CF lung disease and oxidative stress. The defect in CF is the loss of function of the transmembrane conductance regulator (CFTR) protein; recent evidence that CFTR expression and function are modulated by oxidative stress suggests that the loss may result in a poor adaptive response to oxidants. Pancreatic insufficiency in CF also increases susceptibility to deficiencies in lipophilic antioxidants. Finally the airway infection and inflammatory processes in the CF lung are potential sources of oxidants that can affect normal airway physiology and contribute to the mechanisms causing characteristic changes associated with bronchiectasis and loss of lung function. These multiple abnormalities in the oxidant/antioxidant balance raise several possibilities for therapeutic interventions that must be carefully assessed. IntroductionCystic fibrosis (CF) is the most common fatal disease caused by a single gene defect in Europe and North America [1,2]. The defective gene was identified in 1989 [3][4][5] and shown to encode the cystic fibrosis trans-membrane conductance regulator protein (CFTR). CFTR is a cyclic AMP-regulated anion channel with greatest selectivity for chloride, and bicarbonate [6][7][8]. Furthermore, CFTR regulates sodium transport across epithelial membranes through interactions with the epithelial sodium channel ENaC [9], and facilitates the trans-membrane export of the small organic anionic peptide glutathione [10]. The expression of CFTR is located in the apical membrane of epithelial cells that line mucous membranes and submucosal glands ☆ A list of participants may be found in the Acknowledgments.

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Risk Factors for Lung Cancer and for Intervention Effects in CARET, the Beta-Carotene and Retinol Efficacy Trial

Cited by 1,120 publications

References 29 publications

Blood concentrations of carotenoids and retinol and lung cancer risk: an update of the WCRF–AICR systematic review of published prospective studies

Blood concentrations of carotenoids and retinol and lung cancer risk: an update of the WCRF–AICR systematic review of published prospective studies

Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

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