Risk Of Lung Cancer In Nonsmokers Research Articles

Ethnicity-specific association between TERT rs2736100 (A > C) polymorphism and lung cancer risk: a comprehensive meta-analysis

The rs2736100 (A > C) polymorphism of the second intron of Telomerase reverse transcriptase (TERT) has been confirmed to be closely associated with the risk of Lung cancer (LC), but there is still no unified conclusion on the results of its association with LC. This study included Genome-wide association studies (GWAS) and case–control studies reported so far on this association between TERT rs2736100 polymorphism and LC to clarify such a correlation with LC and the differences in it between different ethnicities and different types of LC. Relevant literatures published before May 7, 2022 on ‘TERT rs2736100 polymorphism and LC susceptibility’ in PubMed, EMbase, CENTRAL, MEDLINE databases were searched through the Internet, and data were extracted. Statistical analysis of data was performed in Revman5.3 software, including drawing forest diagrams, drawing funnel diagrams and so on. Sensitivity and publication bias analysis were performed in Stata 12.0 software. The C allele of TERT rs2736100 was associated with the risk of LC (Overall population: [OR] = 1.21, 95%CI [1.17, 1.25]; Caucasians: [OR] = 1.11, 95%CI [1.06, 1.17]; Asians: [OR] = 1.26, 95%CI [1.21, 1.30]), and Asians had a higher risk of LC than Caucasians (C vs. A: Caucasians: [OR] = 1.11 /Asians: [OR]) = 1.26). The other gene models also showed similar results. The results of stratified analysis of LC patients showed that the C allele was associated with the risk of Non-small-cell lung carcinoma (NSCLC) and Lung adenocarcinoma (LUAD), and the risk of NSCLC and LUAD in Asians was higher than that in Caucasians. The C allele was associated with the risk of Lung squamous cell carcinoma (LUSC) and Small cell lung carcinoma(SCLC) in Asians but not in Caucasians. NSCLC patients ([OR] = 1.27) had a stronger correlation than SCLC patients ([OR] = 1.03), and LUAD patients ([OR] = 1.32) had a stronger correlation than LUSC patients ([OR] = 1.09).In addition, the C allele of TERT rs2736100 was associated with the risk of LC, NSCLC and LUAD in both smoking groups and non-smoking groups, and the risk of LC in non-smokers of different ethnic groups was higher than that in smokers. In the Asians, non-smoking women were more at risk of developing LUAD. The C allele of TERT rs2736100 is a risk factor for LC, NSCLC, and LUAD in different ethnic groups, and the Asian population is at a more common risk. The C allele is a risk factor for LUSC and SCLC in Asians but not in Caucasians. And smoking is not the most critical factor that causes variation in TERT rs2736100 to increase the risk of most LC (NSCLC, LUAD). Therefore, LC is a multi-etiological disease caused by a combination of genetic, environmental and lifestyle factors.

Sex disparity of lung cancer risk in non-smokers: a multicenter population-based prospective study based on China National Lung Cancer Screening Program.

Background:Non-smokers account for a large proportion of lung cancer patients, especially in Asia, but the attention paid to them is limited compared with smokers. In non-smokers, males display a risk for lung cancer incidence distinct from the females—even after excluding the influence of smoking; but the knowledge regarding the factors causing the difference is sparse. Based on a large multicenter prospective cancer screening cohort in China, we aimed to elucidate the interpretable sex differences caused by known factors and provide clues for primary and secondary prevention.Methods:Risk factors including demographic characteristics, lifestyle factors, family history of cancer, and baseline comorbidity were obtained from 796,283 Chinese non-smoking participants by the baseline risk assessment completed in 2013 to 2018. Cox regression analysis was performed to assess the sex difference in the risk of lung cancer, and the hazard ratios (HRs) that were adjusted for different known factors were calculated and compared to determine the proportion of excess risk and to explain the existing risk factors.Results:With a median follow-up of 4.80 years, 3351 subjects who were diagnosed with lung cancer were selected in the analysis. The lung cancer risk of males was significantly higher than that of females; the HRs in all male non-smokers were 1.29 (95% confidence interval [CI]: 1.20–1.38) after adjusting for the age and 1.38 (95% CI: 1.28–1.50) after adjusting for all factors, which suggested that known factors could not explain the sex difference in the risk of lung cancer in non-smokers. Known factors were 7% (|1.29–1.38|/1.29) more harmful in women than in men. For adenocarcinoma, women showed excess risk higher than men, contrary to squamous cell carcinoma; after adjusting for all factors, 47% ([1.30–1.16]/[1.30–1]) and 4% ([7.02–6.75]/[7.02–1])) of the excess risk was explainable in adenocarcinoma and squamous cell carcinoma. The main causes of gender differences in lung cancer risk were lifestyle factors, baseline comorbidity, and family history.Conclusions:Significant gender differences in the risk of lung cancer were discovered in China non-smokers. Existing risk factors did not explain the excess lung cancer risk of all non-smoking men, and the internal causes for the excess risk still need to be explored; most known risk factors were more harmful to non-smoking women; further exploring the causes of the sex difference would help to improve the prevention and screening programs and protect the non-smoking males from lung cancers.

Construction and Validation of a Lung Cancer Risk Prediction Model for Non-Smokers in China.

BackgroundAbout 15% of lung cancers in men and 53% in women are not attributable to smoking worldwide. The aim was to develop and validate a simple and non-invasive model which could assess and stratify lung cancer risk in non-smokers in China.MethodsA large-sample size, population-based study was conducted under the framework of the Cancer Screening Program in Urban China (CanSPUC). Data on the lung cancer screening in Henan province, China, from October 2013 to October 2019 were used and randomly divided into the training and validation sets. Related risk factors were identified through multivariable Cox regression analysis, followed by establishment of risk prediction nomogram. Discrimination [area under the curve (AUC)] and calibration were further performed to assess the validation of risk prediction nomogram in the training set, and then validated by the validation set.ResultsA total of 214,764 eligible subjects were included, with a mean age of 55.19 years. Subjects were randomly divided into the training (107,382) and validation (107,382) sets. Elder age, being male, a low education level, family history of lung cancer, history of tuberculosis, and without a history of hyperlipidemia were the independent risk factors for lung cancer. Using these six variables, we plotted 1-year, 3-year, and 5-year lung cancer risk prediction nomogram. The AUC was 0.753, 0.752, and 0.755 for the 1-, 3- and 5-year lung cancer risk in the training set, respectively. In the validation set, the model showed a moderate predictive discrimination, with the AUC was 0.668, 0.678, and 0.685 for the 1-, 3- and 5-year lung cancer risk.ConclusionsWe developed and validated a simple and non-invasive lung cancer risk model in non-smokers. This model can be applied to identify and triage patients at high risk for developing lung cancers in non-smokers.

Abstract CN14-01: A genome-wide association study identifies variation in nicotine acetylcholine receptors that influence risk for lung cancer and smoking behavior

Abstract CN14-01 In order to identify genetic factors that influence risk for developing lung cancer wer performed a genome-wide analysis using 315,450 SNPs queried on 1154 lung cancer cases and 1137 controls. Results from this analysis and follow-up studies involving 2714 lung cancer cases and 3694 controls identified a region on chromosome 15q that contains nicotinic acetylcholine genes as showing an extremely consistent and significant association with lung cancer risk. The genes that are implicated in this region play a role in signal transduction after exposure to nicotine or its metabolites. The associated SNPs were shown by us and others to play a role in smoking behavior, but further detailed analyses have demonstrated an independent effect of this locus on lung cancer risk beyond that which can be explained solely by smoking behavior. These findings support earlier biological studies suggesting a direct role of nicotine or its metabolites in promoting lung cancer development. Variations in the SNPs on chromosome 15 do not associate with lung cancer risk in nonsmokers, indicating a gene-environment interaction. Studies including cases with a family history of lung cancer show a higher risk for lung cancer in this subset of individuals. In a further study, 9531 lung cancer cases and 9674 controls have been queried to identify additional genetic factors that reliably increase lung cancer risk and additional loci on chromosomes 6 and 5 have been identified. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN14-01.

Tagging single nucleotide polymorphisms in MBD4 are associated with risk of lung cancer in a Chinese population

MBD4 (methyl-CpG binding domain protein 4) was identified as a methyl-CpG binding protein and plays an important role in DNA methylation and carcinogenesis. We hypothesized that genetic variants in MBD4 were associated with lung cancer risk. We selected and genotyped three tagging SNPs (rs2311394, rs140693, and rs2005618) of MBD4 using the illumina SNP genotyping BeadLab platform in a case-control study of 500 incident lung cancer patients and 517 cancer-free controls in a Chinese population. We observed a significantly decreased risk of lung cancer associated with the rs140693 GA genotype (adjusted OR=0.70, 95% CI=0.52-0.93), and the combined rs140693 GA/AA variant genotypes (adjusted OR=0.76, 95% CI=0.58-1.00), compared with the wild-type homozygote rs140693 GG. The reduced lung cancer risk in non-smokers carrying rs140693 GA/AA genotypes was more predominant (adjusted OR=0.56, 95% CI=0.35-0.87). However, there was no statistic evidence of gene-smoking interaction. These findings suggest that genetic variants of MBD4 rs140693 may modulate risk of lung cancer. Further larger case-control and functional studies are needed to validate these findings.

Metabolic gene polymorphisms and lung cancer risk in non-smokers: An update of the GSEC study

Background Since genetic factors may play an important role in lung cancer development at low dose carcinogen exposure, non-smokers are a good model to study genetic susceptibility and its interaction with environmental factors. Materials and methods We evaluated the role of the metabolic gene polymorphisms CYP1A1MspI, CYP1A1Ile 462 Val, GSTM1, and GSTT1 in non-smoker lung cancer patients from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Non-smokers (defined as subjects who never smoked on a regular basis) were selected from the GSEC database. We pooled the raw data from 21 case-control studies for a total of 2764 Caucasians (555 cases and 2209 controls) and 383 Asians (113 cases and 270 controls). Tests of heterogeneity and of inclusion bias were performed. Results A significant association between lung cancer and CYP1A1Ile 462 Val polymorphism was observed in Caucasians (adjusted OR = 2.04, 95% CI 1.17–3.54). GSTT1 deletion seems to be a risk factor for lung cancer in Caucasian non smokers only when the analysis was restricted to studies including healthy controls (adjusted OR = 1.66, 95% CI 1.12–2.46). A protective effect on lung cancer was observed with the combination of CYP1A1 wild type, GSTM1 null, and GSTT1 non-null genotypes. None of the analysed polymorphisms were associated with lung cancer in Asian non-smokers. Discussion Our analysis confirms previous findings that CYP1A1Ile 462 Val polymorphism may play a role in lung carcinogenesis in Caucasian non-smokers.

Exon 5 polymorphisms in the O6-alkylguanine DNA alkyltransferase gene and lung cancer risk in non-smokers exposed to second-hand smoke.

The objective of the study was to examine the association of three exon 5 variants in the O(6)-alkylguanine DNA alkyltransferase (AGT) gene involved in the repair of the mutagenic DNA lesion O(6)-alkylguanine formed by nitrosamines, with lung cancer risk in never-smokers. Exon 5 of the AGT gene was sequenced in genomic DNA from 136 cases and 133 hospital- or population-based controls for whom questionnaire information on second-hand smoke and diet was available to determine the frequencies of the Gly(160)Arg, Ile(143)Val, and Lys(178)Arg variant alleles. No codon (160)Arg variant alleles were found in the study population. The codon (143)Val and (178)Arg variant alleles, present at allele frequencies of 0.07, showed 100% linkage. The odds ratio (OR) of lung cancer for these variant carriers was 2.05 [95% confidence interval (CI) 1.03-4.07]. The risk varied between the different lung cancer pathologies with an increased risk for adenocarcinoma (OR 2.67, 95% CI 1.21-5.87) or small cell carcinoma (OR 4.83, 95% CI 0.91-25.7) but not for squamous cell carcinoma (OR 1.07, 95% CI 0.27-4.18). Compared with individuals carrying the mutant alleles unexposed to second-hand smoke, the OR for exposed variant carriers was 1.95 (95% CI 0.53-1.15); a similar interaction, although not significative, was observed for low consumption of cruciferous vegetables and for green vegetables and tomatoes. These results point toward a role of AGT polymorphisms in lung cancer susceptibility among never-smokers, in particular among subjects exposed to environmental carcinogens.

Diet, reproductive factors and lung cancer risk among Chinese women in Singapore: evidence for a protective effect of soy in nonsmokers.

The factors associated with risk of lung cancer among nonsmokers have not been fully elucidated, but dietary factors have consistently been shown to play a role. Chinese women are unique in having a high incidence of lung cancer despite a low smoking prevalence. This population is also known to have a high intake of soy, a dietary source of phytoestrogens. We conducted a hospital-based case-control study among Singapore Chinese women, comprising 303 cases and 765 age-matched controls, of whom 176 cases and 663 controls were lifetime nonsmokers. Data on demographic background, reproductive factors and dietary intake of fruit, vegetables and soy foods were obtained by in-person interview. We observed an inverse association between intake of total, cruciferous and non-cruciferous vegetables and risk of lung cancer among smokers. Although smokers in the highest tertile of fruit intake also had a lower risk, this was not statistically significant. Higher intake of soy foods significantly reduced risk of lung cancer among lifetime nonsmokers, but not among smokers. When soy isoflavonoid intake in mg/week was computed based on frequency and portion size of intake of eight common local soy foods, the adjusted OR among nonsmokers for the highest tertile compared to the lowest was 0.56, 95% CI 0.37-0.85 (p for trend <0.01). Fruit intake was also significantly associated with reduced lung cancer risk among nonsmokers, but the effect was not significant after adjustment for soy intake. On the other hand, soy intake remained an independent predictor of risk after controlling for fruit intake. Reproductive effects were also primarily confined to lifetime nonsmokers, among whom having 3 or more livebirths (adjusted OR 0.65, 0.44-0.96) and a menstrual cycle length of more than 30 days (OR 0.46, 0.25-0.84) accorded a significantly reduced risk of lung cancer. Place of birth was significantly associated with risk among nonsmokers (OR 2.6, 1.7-3.9 for China-born vs. local born) but not among smokers. When analysis was restricted to nonsmokers with adenocarcinomas, the dietary effects were consistent or enhanced. On stepwise regression, soy intake and cycle length emerged as the independent dietary and reproductive predictors of lung cancer risk in nonsmokers. These findings are consistent with other evidence suggesting an involvement of estrogen-related pathways in lung cancer among non-smoking women.

Revisiting the Association between Environmental Tobacco Smoke Exposure and Lung Cancer Risk

Analyses are described estimating the extent to which confounding by dietary variables and education might bias the reported association of smoking by the husband with lung cancer risk in non-smoking women. For each of the four variables fruit, vegetable and dietary fat consumption and education, independent estimates of their relationships with lung cancer risk in non-smokers were combined by meta-analysis. The risks were estimated as 0.83 per standard deviation [SD, 95% confidence interval (CI) = 0.74–0.93, based on n = 9 studies] for fruit consumption, as 0.84 per SD (CI = 0.75–0.93, n = 11) for vegetable consumption, as 1.17 per SD (CI = 1.08–1.26, n = 7) for dietary fat consumption and as 0.92 per year (CI = 0.89–0.96, n = 17) for education. For each of the same four variables independent estimates of the difference between non-smokers exposed or unexposed to environmental tobacco smoke at home were also combined. Using unweighted means, the differences were estimated as –0.1752 SDs for fruit, –0.0460 SDs for vegetables, +0.1750 SDs for dietary fat and –0.5174 years for education (n = 11, 17, 14 and 15). Using weighted means the differences were –0.0986 SDs for fruit, –0.0387 SDs for vegetables, –0.0464 SDs for dietary fat and –0.1023 for education. The weighted estimates are dominated by one very large study whose results, particularly for dietary fat and education, differed from those seen in the other studies. Using these data and methodology developed to account for confounding by multiple correlated variables, simultaneous adjustment for fruit, vegetables, dietary fat and education is estimated to reduce the increase in lung cancer risk associated with each 10 cigarettes/day smoked by the husband from 10% (95% CI 5–15%) to 6% (1–11%) using unweighted means or to 9% (5–14%) using weighted means. Uncertainties in the estimation procedure are discussed. Other sources of bias will be considered in later papers in this series.

Revisiting the Association between Environmental Tobacco Smoke Exposure and Lung Cancer Risk

Analyses are described estimating the extent to which confounding by dietary variables and education might bias the reported association of smoking by the husband with lung cancer risk in non-smoking women. For each of the four variables fruit, vegetable and dietary fat con sumption and education, independent estimates of their relationships with lung cancer risk in non-smokers were combined by meta-analysis. The risks were estimated as 0.83 per standard deviation [SD, 95% confidence interval (CI) = 0.74-0.93, based on n = 9 studies] for fruit con sumption, as 0.84 per SD (Cl = 0.75-0.93, n = 11) for vege table consumption, as 1.17 per SD (Cl = 1.08-1.26, n = 7) for dietary fat consumption and as 0.92 per year (Cl = 0.89-0.96, n = 17) for education. For each of the same four variables independent estimates of the difference between non-smokers exposed or unexposed to envi ronmental tobacco smoke at home were also combined. Using unweighted means, the differences were esti mated as -0.1752 SDs for fruit, -0.0460 SDs for vegeta bles, +0.1750 SDs for dietary fat and -0.5174 years for education (n = 11, 17, 14 and 15). Using weighted means the differences were -0.0986 SDs for fruit, -0.0387 SDs for vegetables, -0.0464 SDs for dietary fat and -0.1023 for education. The weighted estimates are dominated by one very large study whose results, particularly for dietary fat and education, differed from those seen in the other studies. Using these data and methodology devel oped to account for confounding by multiple correlated variables, simultaneous adjustment for fruit, vegetables, dietary fat and education is estimated to reduce the increase in lung cancer risk associated with each 10 ciga rettes/day smoked by the husband from 10% (95% Cl 5- 15%) to 6% (1-11%) using unweighted means or to 9% (5-14%) using weighted means. Uncertainties in the esti mation procedure are discussed. Other sources of bias will be considered in later papers in this series.

Environmental tobacco smoke and lung cancer: a case-control study in Germany.

To assess the association between exposure to environmental tobacco smoke (ETS) and lung cancer, the authors personally interviewed 292 lifelong nonsmoking lung cancer cases (recruited from 15 hospitals in the study area) and 1,338 nonsmoking controls (randomly selected by population registries) between 1990 and 1996 in Germany. Subjects were asked by a standardized questionnaire about exposure to ETS in childhood, by spouse, at work, and in transportation and social settings. Several indicators of these different sources of exposure were investigated, using not or low exposed subjects as the reference category. The most informative quantification index was weighted duration of exposure (hours x level of smokiness). No effect of ETS exposure during childhood and no clear effect of spousal ETS were observed. However, for the highest category of exposure, clear effects of ETS at the workplace (odds ratio (OR) = 1.93; 95% confidence interval (CI): 1.04, 3.58), in vehicles (OR = 2.64; 95% CI: 1.30, 5.36), and from all sources combined (OR = 1.39; 95% CI: 0.96, 2.01) were found. Adjustment for occupational carcinogens, radon, and diet did not appreciably change the results. These findings suggest that exposures to high levels of ETS at the workplace and in other public indoor settings appear to be important risk factors for lung cancer risk in nonsmokers.

Environmental tobacco smoke and lung cancer risk: Epidemiology in relation to confounding factors

This review discusses the many confounding risk factors likely to be relevant when assessing the risk of lung cancer in nonsmokers exposed to environmental tobacco smoke (ETS). The literature reflects wide recognition that confounding factors must be considered in assessing the causal implications of evidence from epidemiological studies, especially in studies where the calculated relative risks are less than two-fold. Numerous risk factors for lung cancer have been identified in the literature and are summarized in this review. Many of those risk factors are relatively much greater than those that have been associated with ETS exposure, yet none of the epidemiological studies nor the principal overviews associating ETS with lung cancer risk in nonsmokers has been found to make appropriate adjustments for confounders. It seems likely that the additive effect of the many confounders and other risk factors already found to increase lung cancer risk by factors of 2 to more than 20 could explain the relative risk values that have been observed in the epidemiological studies and reviews based on spousal smoking.

Lung cancer and passive smoking: Association an artefact due to misclassification of smoking habits?

1775 subjects were asked about their current use of tobacco products or nicotine chewing gum. 1537 provided a sample of saliva for cotinine analysis. Of 808 who claimed not to be users of such products, 20 (2.5%) had cotinine values above 30 ng ml , suggesting their self-reports were false. In another study, 540 subjects were interviewed on two occasions. 10% of subjects claiming on one occasion never to have smoked made inconsistent statements on the other occasion. A third study showed a strong tendency for smokers to marry smokers. Bias caused by misclassification of smoking habits coupled with between-spouse smoking habit concordance can completely explain reported apparent excesses in lung cancer risk in non-smokers married to smokers.