Investigating the relationship between β-carotene intake from diet and supplements, smoking, and lung cancer risk

Hypomethylation of cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is consistently and strongly associated with higher exposure to smoking (e.g., current smoking, greater number of pack years, and less time since quitting). Although cg05575921 hypomethylation has been reported to be associated with lung cancer risk and mortality, this has not been explored within heavy smokers or by histotype. We assessed cg05575921 methylation for associations with smoking behavior, prospective lung cancer risk, and mortality in 313 cases and controls from the Beta Carotene and Retinol Efficacy Trial (CARET) with ≥20 pack years of smoking and matched on age (±5 years), sex, race/ethnicity, enrollment year, smoking status, occupational asbestos exposure, and follow-up time. Methylation of cg05575921 in blood collected on average 4.3 years prior to diagnosis in cases was assayed using the 850K Illumina EPIC array. Quintiles of cg05575921 methylation were defined based on the control distribution, with the lowest quintile (Q1, referent) representing hypermethylation and the highest (Q5), hypomethylation. Among controls, increasing quintiles of cg05575921 hypomethylation were associated with current smoking status (Cochran-Armitage trend p=3.0 × 10-21), and with decreasing years since last smoked, increasing cigarettes per day, and decreasing body mass index (BMI) (ordinal ANOVA p=3.1 × 10-21, 1.3 × 10-17, and 0.002, respectively). We observed similar patterns in cases. We evaluated associations between cg05575921 methylation and lung cancer risk using logistic regression models conditioned on matching factors and adjusted for age, years since quit, and BMI. We evaluated cg05575921 methylation and lung cancer-specific mortality using Cox proportional hazards models adjusted for stage, age, sex, race, smoking status, intervention arm, asbestos exposure, and pack years smoked. We did not observe clear patterns of associations between cg05575921 methylation and lung cancer risk overall or by histotype. However, we found a linear relationship (p=0.03) between increasing cg05575921 hypomethylation and overall lung cancer mortality, with Q5 vs Q1 Hazard Ratio (HR)=1.60 (95% Confidence Interval (95% CI): 1.00-2.57) for mortality from lung cancer overall, and HR=2.09, 95% CI: 0.96-4.54 for adenocarcinoma (N=121). Our findings provide preliminary support that even among heavy smokers, cg05575921 hypomethylation is associated with more recent and extensive exposure to cigarette smoking, and that prediagnosis cg05575921 hypomethylation in lung cancer cases is associated with an increased hazard of death. However, since the CARET population represents a group who would largely qualify for lung cancer screening with annual low-dose computed tomography per the United States Preventive Task Force guidelines, our results do not provide support for the use of cg05575921 hypomethylation as an indicator for screening-based lung cancer risk stratification. Citation Format: Stefan Graw, Matt J. Barnett, Mark D. Thornquist, Gary E. Goodman, Chu Chen, Devin C. Koestler, Carmen J. Marsit, Jennifer A. Doherty, Laurie Grieshober. AHRR hypomethylation in heavy smokers: Associations with lung cancer risk and mortality [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A20.

While diets rich in fruit and vegetables appear to reduce lung cancer risk, the evidence for individual carotenoid and vitamin intakes has been judged too limited to reach firm conclusions. Data from a case–control study of lung cancer (Montreal, QC, Canada, 1996–2002) were used to investigate the role of dietary intakes of β-carotene, α-carotene, β-cryptoxanthin, lutein/zeaxanthin, lycopene, and vitamin C in lung cancer risk. In-person interviews elicited dietary information from 1,105 incident cases and 1,449 population controls. Usual frequency of consumption of 49 fruits and vegetables 2 years prior to diagnosis/interview was collected. Odds ratios (ORs) and 95% confidence intervals (CIs) between intake variables and lung cancer were estimated using logistic or polytomous regression, adjusting for potential confounding factors including a detailed smoking history. ORs associated with upper versus lower tertiles of intake were 0.66 (95% CI = 0.51–0.84) for β-carotene, 0.70 (95% CI = 0.55–0.90) for α-carotene, 0.65 (95% CI = 0.51–0.84) for β-cryptoxanthin, 0.75 (95% CI = 0.59–0.95) for lycopene, and 0.74 (95% CI = 0.58–0.96) for vitamin C. ORs suggestive of a protective effect were found for elevated intakes of β-carotene, α-carotene, β-cryptoxanthin, and lycopene in male heavy smokers and of vitamin C in female heavy smokers. Selected antioxidants were also associated with a lower risk of lung cancer in female moderate smokers, and of squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. These results suggest that several dietary antioxidants found in common food sources may protect against lung cancer, even among heavy smokers.

Subject index

The objective of the current study was to estimate the risk of lung cancer attributable to occupational factors and not due to tobacco. At 24 hospitals in nine metropolitan areas in the United States, 1793 male lung cancer cases were matched for race, age, hospital, year of interview, and cigarette smoking (never smoker, ex-smoker, smoker (1-19 and > or = 20 cigarettes per day)) to two types of controls (cancer and non-cancer hospital patients). Information on usual occupation, exposure to specific potential carcinogens, and cigarette smoking was obtained by interview. Risk of lung cancer was increased significantly for electricians; sheetmetal workers and tinsmiths; bookbinders and related printing trade workers; cranemen, derrickmen, and hoistmen; moulders, heat treaters, annealers and other heated metal workers; and construction labourers. All of these occupations are potentially exposed to known carcinogens. Odds ratios (ORs) were increased for exposure to coal dust (adjusted OR = 1.5; 95% confidence interval (95% CI) 1.1-2.1). After stratification, this association was statistically significant only after 10 or more years of exposure. Lung cancer was also related to exposure to asbestos (adjusted OR = 1.8; 95% CI 1.5-2.2). The ORs increased with increasing duration of exposure to asbestos for all smoking categories except for current smokers of 1-19 cigarettes per day. The statistical power to detect ORs among occupations that were previously reported to be at increased risk of lung cancer but that failed to show an OR of at least 1.5 in the current study was small. The cumulative population attributable risk (PAR) of lung cancer due to occupation was 9.2%. It is concluded that occupational factors play an important part in the development of lung cancer independently of cigarette smoking. Because occupations at high risk of lung cancer were under-represented, the cumulative PAR of the present study is likely to be an underestimate of the true contribution of occupation to risk of lung cancer.

α1-Antitrypsin and Neutrophil Elastase Imbalance and Lung Cancer Risk

Heavy industrial exposure to asbestos causes lung cancer and mesothelioma, but it remains unknown whether much lower environmental exposure to asbestos also causes these cancers. Nevertheless, regulatory agencies, including the Environmental Protection Agency (EPA), have assessed the risk of lung cancer by extrapolating known risks from past industrial exposure to asbestos to today's much lower environmental asbestos levels (roughly 100,000 times lower). We also tested the EPA's model for predicting the risk of asbestos-induced lung cancer in a population of women with relatively high levels of nonoccupational exposure to asbestos. Mortality among women in 2 chrysotile-asbestos-mining areas of the province of Quebec was compared with mortality among women in 60 control areas, and age-standardized mortality ratios were derived. With the help of an expert panel, we estimated past exposure to asbestos among women in the mining areas and used these data with the EPA's model to predict the relative risk of lung cancer. We then compared this prediction with the observed mortality ratios. On the basis of the estimated exposure in the asbestos-mining areas, a relative risk of death due to lung cancer of 2.1 was predicted by the EPA's model, amounting to about 75 excess deaths from lung cancer in this population. By contrast, we calculated a standardized mortality ratio of 1.0 and a standardized proportionate mortality ratio of 1.1 (P> 0.05), suggesting that there were between 0 and 6.5 excess deaths from lung cancer among the women with nonoccupational exposure to asbestos. Seven deaths from pleural cancer were observed (relative risk=7.63; P<0.05). We found no measurable excess risk of death due to lung cancer among women in two chrysotile-asbestos-mining regions. The EPA's model overestimated the risk of asbestos-induced lung cancer by at least a factor of 10.

BackgroundObservational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks.MethodsOur primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse‐variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided.ResultsThe genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups.ConclusionsGenetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

The Life Span Study of Japanese atomic bomb survivors estimated greater risks of radiation-associated lung cancer among females than males, with direct implications for occupational radiation safety policy. To evaluate replicability of these findings in radiation workers, we assessed sex-specific radiation-associated risks of lung cancer mortality in a large cohort of US radiological technologists. Using data from 4 questionnaires (1983-2013), we reconstructed lifetime smoking history for 83 715 female and 26 650 male technologists. We estimated individual lung occupational radiation doses using badge dose and questionnaire data. We used Poisson regression to investigate joint radiation-smoking effects on sex-averaged and sex-specific lung cancer mortality risk. For 1243 female and 607 male technologists who died from lung cancer, median cumulative lung dose was 16.2 mGy (non-cases: 7.7 mGy) and 24.5 mGy (non-cases: 10.1 mGy), respectively. Excess risk of lung cancer increased with increasing radiation dose. However, smoking modified this effect: the radiation effect at 100 mGy increased until 16 cigarettes/day, after which it declined. Excess relative risk (ERR) per 100 mGy was greater among males (never smoking additive ERR = 1.98; 95% CI = 0.34 to 6.25) than females (never smoking additive ERR = 0.40; 95% CI = -0.02 to 1.21); sex differences persisted up to ∼40 cigarettes/day. Our results indicated radiation-associated risks of lung cancer mortality were stronger in males than females, in contrast to the Life Span Study. However, both studies found radiation-associated risks were highest in workers with light-to-moderate smoking intensity. Altogether, these findings reinforce the importance of rigorous radiation protection measures for all radiation workers, regardless of sex, alongside interventions to support smoking cessation.

Methyl-CpG binding domain 4 (MBD4) protein functions as a DNA repair enzyme and minimizes mutations at 5-methylcytosine. Polymorphisms in the DNA repair gene MBD4 may be associated with differences in DNA repair capacity and thereby influence an individual's susceptibility to lung cancer. To test this hypothesis, we examined the potential association between the MBD4 Glu346Lys polymorphism and the risk of lung cancer in a Korean population. The MBD4 Glu346Lys genotypes were determined in 432 lung cancer patients and 432 healthy age- and gender-matched control subjects. The distribution of the MBD4 Glu346Lys genotypes was not significantly different between the overall lung cancer cases and the controls. However, when the cases were categorized by tumor histology, the Lys346Lys genotype was associated with a significantly decreased risk of adenocarcinoma (AC) as compared with the Glu346Glu genotype [adjusted odds ratio (OR) = 0.50, 95% confidence interval (CI) = 0.26-0.97, P = 0.04]. On the stratification analysis, the protective effect of the Lys346Lys genotype against AC was statistically significant in older individuals and heavier smokers (adjusted OR = 0.08, 95% CI = 0.01-0.64, P = 0.02; and adjusted OR = 0.09, 95% CI = 0.01-0.72, P = 0.02, respectively). Our findings suggest that the MBD4 Glu346Lys polymorphism could be used as a marker for genetic susceptibility to AC of the lung.

Ten-year mortality rates for lung cancer and coronary heart disease have been related to cigarette smoking habits in 17 475 male civil servants aged 40-64 and in sample of 8089 male British residents aged 35-69. Both diseases were more frequent in smokers. Lung cancer rates were higher overall for "non-inhalers", particularly in heavy smokers. Tar yield correlated with the risk of lung cancer in non-inhalers but less so in inhalers. Conversely, coronary deaths were more common among inhalers, and the effect of tar/nicotine yield (such as it was) was confined to inhalers. It appears that there are subtle interactions between the amount smoked, the tar/nicotine yield of the cigarette, and the style of smoking. Thus the effects of a change in cigarette characteristics are hard to predict, and they may be different for respiratory and cardiovascular disease.

A high level of available tissue iron may increase the risk of cancer through its contribution to the production of free oxygen radicals. Serum iron, total iron-binding capacity (TIBC) and transferrin saturation levels were studied for their prediction of different cancers in a cohort of 41,276 men and women aged 20-74 years and initially free from cancer. During a mean follow-up of 14 years, 2,469 primary cancer cases were diagnosed. Excess risks of colorectal and lung cancers were found in subjects with transferrin saturation level exceeding 60%. The relative risks, adjusted for age, sex and smoking, were 3.04 for colorectal cancer and 1.51 for lung cancer, in comparison with subjects having lower levels. The risk of lung cancer was inversely related to serum TIBC, with a relative risk between the highest and lowest quartiles of 0.69 for men and 0.19 for women. For the risk of stomach cancer, we detected inverse relationships with serum iron and with transferrin saturation and a positive relationship with TIBC, but these associations weakened when the cancer cases occurring during the 5 first years of follow-up were excluded. High iron stores may increase the risk of colorectal cancer, whereas low iron stores may be an early sign of occult stomach cancer.

Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures.

IntroductionRecently, genome-wide association studies (GWAS) in Caucasian populations have identified an association between single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25, lung cancer risk and smoking behaviors. However, these SNPs are rare in Asians, and there is currently no consensus on whether SNPs in CHRNA5-A3-B4 have a direct or indirect carcinogenic effect through smoking behaviors on lung cancer risk. Though some studies confirmed rs6495308 polymorphisms to be associated with smoking behaviors and lung cancer, no research was conducted in China. Using a case-control study, we decided to investigate the associations between CHRNA3 rs6495308, CHRNB4 rs11072768, smoking behaviors and lung cancer risk, as well as explore whether the two SNPs have a direct or indirect carcinogenic effect on lung cancer.MethodsA total of 1025 males were interviewed using a structured questionnaire (204 male lung cancer patients and 821 healthy men) to acquire socio-demographic status and smoking behaviors. Venous blood samples were collected to measure rs6495308 and rs11072768 gene polymorphisms. All subjects were divided into 3 groups: non-smokers, light smokers (1–15 cigarettes per day) and heavy smokers (>15 cigarettes per day).ResultsCompared to wild genotype, rs6495308 and rs11072768 variant genotypes reported smoking more cigarettes per day and a higher pack-years of smoking (P<0.05). More importantly, among smokers, both rs6495308 CT/TT and rs11072768 GT/GG had a higher risk of lung cancer compared to wild genotype without adjusting for potential confounding factors (OR = 1.36, 95%CI = 1.09–1.95; OR = 1.11, 95%CI = 1.07–1.58 respectively). Furthermore, heavy smokers with rs6495308 or rs11072768 variant genotypes have a positive interactive effect on lung cancer after adjustment for potential confounding factors (OR = 1.13, 95%CI = 1.01–3.09; OR = 1.09, 95%CI = 1.01–3.41 respectively). However, No significant associations were found between lung cancer risk and both rs6495308 and rs11072768 genotypes among non-smokers and smokers after adjusting for age, occupation, and education.ConclusionThis study confirmed both rs6495308 and rs11072768 gene polymorphisms association with smoking behaviors and had an indirect link between gene polymorphisms and lung cancer risk.

Alcoholism and Risk of Lung Cancer in Observational Studies: A Systematic Review

Background The global prevalence of chronic obstructive pulmonary disease (COPD) is increasing, and the risk of lung cancer in these patients is high. The use of inhaled corticosteroids (ICSs) in COPD patients could help to decrease potential lung cancer risk. We planned to conduct this systematic review and meta-analysis to determine the role of ICS in the risk of lung cancer among COPD patients. Methods A comprehensive search of PubMed, Science Direct, Google Scholar, and Cochrane library and a manual search of the list of references were conducted. Studies with cohort, case-control, and randomized clinical trial designs for any ICS use reporting the incidence/hazard ratio (HR) of lung cancer were included. The random-effects model was used to pool hazard ratios. Subgroup analysis and metaregression analysis were employed. Funnel plot and Egger regression test were used to assess publication bias. Results Combining the results of 14 observations, the pooled HR for cancer risk reduction was 0.69 (95% CI 0.59-0.79), p value ≤ 0.001. The use of ICS in COPD patients showed a 31% reduction in the risk of lung cancer. Subgroup meta-analysis showed a significant reduction in the risk of lung cancer as well. Conclusion The use of ICS in COPD patients reduces the risk of lung cancer. The risk reduction was independent of smoking status and latency period. Future studies should focus on the optimum dose and controlling confounders like asthma.