Lung Cancer Risk In Never-smokers Research Articles

Narrative review: respiratory tract microbiome and never smoking lung cancer.

The lung microbiome was previously thought to be a sterile environment where only gaseous exchange takes place, but recent studies have shown the presence of microbiota in the lung. This review investigates the current literature on the effects of an environmental driven dysbiosis on the healthy oral and respiratory microbiome and its relationship to lung cancer risk in never-smokers. An online electronic search was performed on PubMed of all English-language literature using combinations of the following keywords: "lung cancer", "dysbiosis", "non-smokers", "oral microbiome", and "respiratory microbiome". All population-based studies reporting results on oral and/or respiratory microbiome in adults were considered for our narrative review. Metagenomic analyses have been performed on isolated samples from healthy participants and compared to samples from those with lung cancer. Research shows that a decrease in alpha diversity of microbes in the oral microbiome is associated with increased risk of lung cancer, along with differences in beta diversity in the sputum of lung cancer cases and healthy controls. Further, several studies have observed that significant changes in the abundance of genera such as increased abundance of Lactobacillales, Bacilli, and Firmicutes associated with an increased lung cancer risk among participants with exposure to certain household solid fuels. These findings suggest potential carcinogenic processes such as increased inflammation associated with changes in flora. Additionally, studies showed that increase in certain taxa such as Bacteroides and Spirochetes might have a protective effect on lung cancer risk. The review also provides insight into how understanding the microbial changes can be beneficial for lung cancer treatment and disease-free survival. Larger studies in different populations need to be performed to strengthen the current associations between microbial diversity and lung cancer risk.

Lung cancer risk in never-smokers: An overview of environmental and genetic factors.

Lung cancer is the leading cause of cancer-related mortality globally, accounting for 1.8 million deaths in 2020. While the vast majority are caused by tobacco smoking, 15%−25% of all lung cancer cases occur in lifelong never-smokers. The International Agency for Research on Cancer (IARC) has classified multiple agents with sufficient evidence for lung carcinogenesis in humans, which include tobacco smoking, as well as several environmental exposures such as radon, second-hand tobacco smoke, outdoor air pollution, household combustion of coal and several occupational hazards. However, the IARC evaluation had not been stratified based on smoking status, and notably lung cancer in never-smokers (LCINS) has different epidemiological, clinicopathologic and molecular characteristics from lung cancer in ever-smokers. Among several risk factors proposed for the development of LCINS, environmental factors have the most available evidence for their association with LCINS and their roles cannot be overemphasized. Additionally, while initial genetic studies largely focused on lung cancer as a whole, recent studies have also identified genetic risk factors for LCINS. This article presents an overview of several environmental factors associated with LCINS, and some of the emerging evidence for genetic factors associated with LCINS. An increased understanding of the risk factors associated with LCINS not only helps to evaluate a never-smoker’s personal risk for lung cancer, but also has important public health implications for the prevention and early detection of the disease. Conclusive evidence on causal associations could inform longer-term policy reform in a range of areas including occupational health and safety, urban design, energy use and particle emissions, and the importance of considering the impacts of second-hand smoke in tobacco control policy.

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

IntroductionInherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. MethodsWe conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. ResultsWe detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. ConclusionsWe found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

Alcohol consumption and lung cancer risk in never smokers: a pooled analysis of case-control studies.

Lung cancer is the deadliest cancer in developed countries but the etiology of lung cancer risk in never smokers (LCRINS) is largely unknown. We aim to assess the effects of alcohol consumption, in its different forms, on LCRINS. We pooled six multi-center case-control studies developed in the northwest of Spain. Cases and controls groups were composed of never smokers. We selected incident cases with anatomopathologically confirmed lung cancer diagnoses. All participants were personally interviewed. We performed two groups of statistical models, applying unconditional logistic regression with generalized additive models. One considered the effect of alcohol type consumption and the other considered the quantity of each alcoholic beverage consumed. A total of 438 cases and 863 controls were included. Median age was 71 and 66, years, respectively. Adenocarcinoma was the predominant histological type, comprising 66% of all cases. We found that any type of wine consumption posed an OR of 2.20 OR 95%CI 1.12-4.35), and spirits consumption had an OR of 1.90 (95%CI 1.13-3.23). Beer consumption had an OR of 1.33 (95%CI 0.82-2.14). These results were similar when women were analyzed separately, but for men there was no apparent risk for any alcoholic beverage. The dose-response analysis for each alcoholic beverage revealed no clear pattern. Wine and spirits consumption might increase the risk of LCRINSs, particularly in females. These results have to be taken with caution given the limitations of the present study.

A family history of cancer and lung cancer risk in never-smokers: A clinic-based case-control study.

Some population-based studies involving lung cancer patients have reported that inherited susceptibility is responsible for the familial aggregation observed in non-smoking lung cancer patients; however, it has been found that the false-negative rates in clinic-ascertained probands are significantly lower than population-ascertained probands. In this clinic-based study, we sought to determine the relationship between a family history of cancer and lung cancer risk in Chinese never-smokers. In this clinic-based case-control study, all 318 probands and 509 controls were Chinese. The data on demographic characteristics, age, gender, race, lung disease history, living environment, occupational exposure, and smoking history were collected from a structured questionnaire. Multiple conditional logistic regression was used to estimate adjusted odds ratios (aOR) and 95% CIs after adjusting for possible confounders. The risk of lung cancer was increased in individuals with a family history of lung (aOR, 3.21; p<0.001) or any other cancer (aOR, 1.79; p<0.001). Analyses were carried out using stratified relative gender; first-degree female relatives tended to have a higher risk than first-degree male relatives. Similarly, the aOR for a female developing a malignant tumor was two times greater than controls. Our analysis provides further evidence of the importance of genetic factors underlying lung cancer in patients who are never-smokers, especially in patients with a maternal history of cancer.

Lung cancer in never-smokers: a case-control study in a radon-prone area (Galicia, Spain).

The aim of the study was to assess the effect of residential radon exposure on the risk of lung cancer in never-smokers and to ascertain if environmental tobacco smoke modifies the effect of residential radon. We designed a multicentre hospital-based case-control study in a radon-prone area (Galicia, Spain). All participants were never-smokers. Cases had an anatomopathologically confirmed primary lung cancer and controls were recruited from individuals undergoing minor, non-oncological surgery. Residential radon was measured using alpha track detectors. We included 521 individuals, 192 cases and 329 controls, 21% were males. We observed an odds ratio of 2.42 (95% CI 1.45-4.06) for individuals exposed to ≥200 Bq·m(-3) compared with those exposed to <100 Bq·m(-3). Environmental tobacco smoke exposure at home increased lung cancer risk in individuals with radon exposure>200 Bq·m(-3). Individuals exposed to environmental tobacco smoke and to radon concentrations>200 Bq·m(-3) had higher lung cancer risk than those exposed to lower radon concentrations and exposed to environmental tobacco smoke. Residential radon increases lung cancer risk in never-smokers. An association between residential radon exposure and environmental tobacco smoke on the risk of lung cancer might exist.

GSTM1 and GSTT1 copy numbers and mRNA expression in lung cancer

Large fractions of the human population do not express GSTM1 and GSTT1 (GSTM1/T1) enzymes because of deletions in these genes. These variations affect xenobiotic metabolism and have been evaluated in relation to lung cancer risk, mostly based on null/present gene models. We measured GSTM1/T1 heterozygous deletions, not tested in genome-wide association studies, in 2,120 controls and 2,100 cases from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We evaluated their effect on mRNA expression on lung tissue and peripheral blood samples and their association with lung cancer risk overall and by histology types. We tested the null/present, dominant, and additive models using logistic regression. Cigarette smoking and gender were studied as possible modifiers. Gene expression from blood and lung tissue cells was strongly down regulated in subjects carrying GSTM1/T1 deletions by both trend and dominant models (P < 0.001). In contrast to the null/present model, analyses distinguishing subjects with 0, 1, or 2 GSTM1/T1 deletions revealed several associations. There was a decreased lung cancer risk in never-smokers (OR = 0.44; 95%CI = 0.23-0.82; P = 0.01) and women (OR = 0.50; 95%CI = 0.28-0.90; P = 0.02) carrying 1 or 2 GSTM1 deletions. Analogously, male smokers had an increased risk (OR = 1.13; 95%CI = 1.0-1.28; P = 0.05) and women a decreased risk (OR = 0.78; 95%CI = 0.63-0.97; P = 0.02) for increasing GSTT1 deletions. The corresponding gene smoking and gene-gender interactions were significant (P < 0.05). Our results suggest that decreased activity of GSTM1/T1 enzymes elevates lung cancer risk in male smokers, likely due to impaired carcinogens' detoxification. A protective effect of the same mutations may be operative in never-smokers and women, possibly because of reduced activity of other genotoxic chemicals.

GPC5 rs2352028 Polymorphism and Risk of Lung Cancer in Han Chinese

rs2352028 in GPC5 has been reported to be associated with the risk of lung cancer in never-smokers. We performed a replication study in 1,045 lung cancer patients and 1,094 controls of Han Chinese origin. We found no association between rs2352028 and lung cancer/adenocarcinoma in never-smokers, but a p value of .04 (under the recessive model) was obtained between this SNP and overall lung cancer/adenocarcinoma. Our data and a recent meta-analysis suspected the possibility of rs2352028 being a risk variant of lung cancer risk in never-smokers. Our findings suggested that rs2352028 might confer a slight risk to lung cancer/adenocarcinoma.

Chromosome 15q25 (CHRNA3-CHRNA5) Variation Impacts Indirectly on Lung Cancer Risk

Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29–1.62, P = 3.69×10−10) and 1.35 (95% CI: 1.18–1.55, P = 9.99×10−6) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10−5 and P = 5.65×10−3). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating - lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94–1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk.

Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers

Inflammation appears to be important in lung carcinogenesis among smokers, but its role among never-smokers is not well established. We hypothesized that inflammatory medical conditions and gene polymorphisms interact to increase lung cancer risk in never-smokers. We interviewed 433 Singaporean female never-smoker lung cancer patients and 1375 hospital controls, and evaluated six polymorphisms in the interleukin 1-β, interleukin 6 (IL6), cyclooxygenase-2, peroxisome proliferator-activated receptor-γ and interleukin 1-β receptor antagonist (IL1RN) genes. Tuberculosis was associated with a non-significant elevated risk of lung cancer [odds ratio (OR) 1.58, 95% confidence interval (CI) 0.95-2.62]. There was no effect of asthma, atopy or chronic productive cough individually. However, the presence of one or more of these conditions (asthma, cough or atopy) increased risk (OR 2.24, 95%CI 1.15-4.38) in individuals possessing the T/T genotype at interleukin 1-β -31T/C, but not in those possessing the C/T (OR 0.87, 95%CI 0.51-1.57) or C/C genotypes (OR 0.58, 95%CI 0.27-1.27), and in individuals having the *2 variable number of tandem repeat allele of IL1RN [OR 5.09 (1.39-18.67)], but not in those without (OR 0.93, 95%CI 0.63-1.35). The IL6-634 G allele increased the risk of lung cancer (OR 1.44, 95%CI 1.07-1.94). Lung cancer risk also increased with the number of polymorphism sites where at least 1 'risk' allele was present [interleukin 1-β -31T/C (T allele), IL1RN (*2 allele) and IL6-634C/G (G allele)] among those with asthma, cough or atopy (Ptrend 0.001) but not in those without (Ptrend 0.47). Our results suggest that the effect of inflammatory medical conditions on lung cancer in never-smokers is modulated by host genetic susceptibility and will need to be confirmed in other studies conducted in similar populations.

Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors

BackgroundWe conducted a case-control study in the greater Toronto area to evaluate potential lung cancer risk factors including environmental tobacco smoke (ETS) exposure, family history of cancer, indoor air pollution, workplace exposures and history of previous respiratory diseases with special consideration given to never smokers.Methods445 cases (35% of which were never smokers oversampled by design) between the ages of 20-84 were identified through four major tertiary care hospitals in metropolitan Toronto between 1997 and 2002 and were frequency matched on sex and ethnicity with 425 population controls and 523 hospital controls. Unconditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between exposures and lung cancer risk.ResultsAny previous exposure to occupational exposures (OR total population 1.6, 95% CI 1.4-2.1, OR never smokers 2.1, 95% CI 1.3-3.3), a previous diagnosis of emphysema in the total population (OR 4.8, 95% CI 2.0-11.1) or a first degree family member with a previous cancer diagnosis before age 50 among never smokers (OR 1.8, 95% CI 1.0-3.2) were associated with increased lung cancer risk.ConclusionsOccupational exposures and family history of cancer with young onset were important risk factors among never smokers.

Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers

Genome-wide association studies have provided evidence that common variation at 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) influences lung cancer risk. To examine if variation at any of these loci influences the risk of lung cancer in never-smokers, we compared 5p15.33-TERT (rs2736100), 5p15.33-CLPTM1L (rs4975616), 6p21.33-BAT3 (rs3117582), 15q25.1-CHRNA3 (rs8042374) and 15q25.1-CHRNA3 (rs12914385) genotypes in a series of 239 never-smoker lung cancer cases and 553 never-smoker controls. A statistically significant association between lung cancer risk and 5p15.33 genotypes was found: rs2736100 (odds ratio = 0.78, 95% confidence interval: 0.63-0.97; P = 0.02), rs4975616 (odds ratio = 0.69, 95% confidence interval: 0.55-0.85; P = 7.95 x 10(-4)), primarily for adenocarcinoma. There was no evidence of association between 6p21.33 or 15q25.1 variation and risk of lung cancer. This analysis provides evidence that TERT-CLPTM1L variants may influence the risk of lung cancer outside the context of tobacco smoking.

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.

Genetic polymorphisms in DNA repair genes and risk of lung cancer.

Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of lung cancer. The frequencies of several amino acid substitutions in XRCC1 (Arg194Trp, Arg280His and Arg399Gln), XRCC3 (Thr241Met), XPD (Ile199Met, His201Tyr, Asp312Asn and Lys751Gln) and XPF (Pro379Ser) genes were studied in 96 non-small-cell lung cancer (NSCLC) cases and in 96 healthy controls matched for age, gender and cigarette smoking. The XPD codon 312 Asp/Asp genotype was found to have almost twice the risk of lung cancer when the Asp/Asn + Asn/Asn combined genotype served as reference [odds ratio (OR) 1.86, 95% confidence interval (CI), 1.02-3.40]. In light cigarette smokers (less than the median of 34.5 pack-years), the XPD codon 312 Asp/Asp genotype was more frequent among cases than in controls and was associated with an increased risk of NSCLC. Compared with the Asn/Asn carriers, the OR in light smokers with the Asp/Asn genotype was 1.70 (CI0.35 0.43-6.74) and the OR in those with the Asp/Asp genotype was 5.32 (CI0.35-21.02) (P trend = 0.01). The 312 Asp/Asp genotype was not associated with lung cancer risk in never-smokers or heavy smokers (>34.5 pack-years). The XPD-312Asp and -751Lys polymorphisms were in linkage disequilibrium in the group studied; this finding was further supported by pedigree analysis of four families from Utah. The XPD 312Asp amino acid is evolutionarily conserved and is located in the seven-motif helicase domain of the RecQ family of DNA helicases. Our results indicate that these polymorphisms in the XPD gene should be investigated further for the possible attenuation of DNA repair and apoptotic functions and that additional molecular epidemiological studies are warranted to extend these findings.

Environmental tobacco smoke and lung cancer mortality in the American Cancer Society's Cancer Prevention Study. II.

Environmental tobacco smoke (ETS) has been classified as a human lung carcinogen by the United States Environmental Protection Agency (EPA), based both on the chemical similarity of sidestream and mainstream smoke and on slightly higher lung cancer risk in never-smokers whose spouses smoke compared with those married to nonsmokers. We evaluated the relation between ETS and lung cancer prospectively in the US, among 114,286 female and 19,549 male never-smokers, married to smokers, compared with about 77,000 female and 77,000 male never-smokers whose spouses did not smoke. Multivariate analyses, based on 247 lung cancer deaths, controlled for age, race, diet, and occupation. Dose-response analyses were restricted to 92,222 women whose husbands provided complete information on cigarette smoking and date of marriage. Lung cancer death rates, adjusted for other factors, were 20 percent higher among women whose husbands ever smoked during the current marriage than among those married to never-smokers (relative risk [RR] = 1.2, 95 percent confidence interval [CI] = 0.8-1.6). For never-smoking men whose wives smoked, the RR was 1.1 (CI = 0.6-1.8). Risk among women was similar or higher when the husband continued to smoke (RR = 1.2, CI = 0.8-1.8), or smoked 40 or more cigarettes per day (RR = 1.9, CI = 1.0-3.6), but did not increase with years of marriage to a smoker. Most CIs included the null. Although generally not statistically significant, these results agree with the EPA summary estimate that spousal smoking increases lung cancer risk by about 20 percent in never-smoking women. Even large prospective studies have limited statistical power to measure precisely the risk from ETS.