Lung cancer burden attributable to ambient particulate matter: a nationally representative population-based case-control study.

Asbestos Exposure, Asbestosis, and Lung Cancer

Prospective cohort and genome-wide association studies have found consistent associations between longer leukocyte telomere length (LTL) and increased lung cancer risk. These findings present a paradox in the traditional expectations of telomere dynamics in cancer development, as longer telomeres are generally considered to be reflective of less advanced age and greater genomic stability. We posited that longer LTL may reflect or lead to delayed cellular senescence allowing cells to accumulate genomic abnormalities that drive lung carcinogenesis. Furthermore, increased copy number of Alu retroelements, repetitive mobile DNA sequences that are approximately 300 base pairs in length, could also reflect genomic instability. We previously found that exposure to diesel exhaust, a known lung carcinogen, was associated with increased Alu copy number and suspect that increased Alu retrotransposition could influence lung carcinogenesis. However, the interrelationship between Alu retroelements, LTL, and lung cancer is unknown. Therefore, we investigated associations between Alu copy number, LTL, and lung cancer risk in the prospective Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We conducted a nested case-control study of 410 confirmed incident lung cancer cases and 416 controls individually matched on age, sex, race/ethnicity, study center, and blood draw date. Quantitative PCR was used to measure Alu copy number and telomere length relative to albumin (Alb) copy number (Alu/Alb and T/S ratio, respectively) in pre-diagnostic leukocytes. Conditional logistic regression was used to estimate associations between quartiles (Q) of Alu/Alb ratio (reference=Q1) and lung cancer risk, adjusted for matching factors, smoking status and packyears, and LTL. Additionally, we dichotomized Alu/Alb ratio and LTL at their medians and created a cross-combination variable to assess combined effects. We found a positive dose-response relationship between Alu/Alb ratio and lung cancer risk (odds ratio (OR), 95% confidence intervals (CI): Q2: 1.34 (0.73, 2.48); Q3:1.89 (0.94, 3.84); Q4: 2.66 (1.03, 5.63); p-trendordinal=0.02). The association was apparent for lung adenocarcinoma (LUAD) (Q2: 1.32 (0.46, 3.77); Q3: 2.88 (0.90, 9.25); Q4: 5.07 (1.29, 19.87); p-trendordinal=0.02). We have previously reported that longer measured LTL was also associated with an increased risk of LUAD (Q4: 2.82 (1.16-6.85); p-trend=0.011). The combined effect of both a higher Alu/Alb ratio and longer LTL was 6.07 (1.75, 21.04; p=4.5x10-3) for LUAD compared with lower/shorter levels of both. Higher Alu copy number and longer LTL were associated with increased risk of lung cancer, especially LUAD. Our findings require replication. If confirmed, evaluation of Alu copy number and LTL in risk stratification and prediction analyses is warranted. Citation Format: Jason Yat-Yang Wong, Richard Cawthon, Wei Hu, Somayina Ezennia, Shahinaz Gadalla, Charles Breeze, Batel Blechter, Neal Freedman, Wen-Yi Huang, H. Dean Hosgood, Wei Jie Seow, Bryan Bassig, Mohammad Rahman, Richard Hayes, Nathaniel Rothman, Qing Lan. Alu retroelement copy number, leukocyte telomere length, and lung cancer risk in the prospective Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2251.

Decision letter: Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome

Editor's evaluation: Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome

PDS 68: Outdoor air pollution, mortality and morbidity, Exhibition Hall (PDS), Ground floor, August 26, 2019, 10:30 AM - 12:00 PM Background/Aim: Ambient air pollution has been associated with lung cancer but the shape of the exposure-response function - especially at lower exposure levels - is not well described. The aim of this study was to address the relationship between long-term low-level air pollution exposure and lung cancer incidence. Methods: The “Effects of low level air pollution: A study in Europe” (ELAPSE) collaboration pools 7 cohorts from across Europe. We developed hybrid models combining monitoring and land use data, satellite observations, and dispersion model estimates for nitrogen dioxide (NO2), fine particulate matter (PM2.5), black carbon (BC), and ozone (O3) to assign exposure to participants’ residential addresses. We analyzed the pooled data by stratified Cox proportional hazards models adjusting for potential confounders. We developed linear and natural cubic spline models, analyses based on subsets and thresholds across the exposure distribution, and multi-pollutant models to disentangle potential inter-dependencies between pollutants. Results: A total of 307,550 persons were included in the analyses. During a mean follow-up of 18.1 years, 3,956 incident lung cancer cases occurred. Median (5–95%) exposure levels of NO2, PM2.5, BC and O3 (warm season) were 24.2 µg/m3 (12.8–39.5), 15.4 µg/m3 (8.7–19.4), 1.6 10-5/m (0.7–2.1), and 86.6 µg/m3 (70.4–92.9), respectively. We observed a higher risk for lung cancer with higher exposure to PM2.5 (HR 1.13, 95% 1.05-1.23 per 5 µg/m3) after adjustment for covariates. The association was similar across subsets of exposure-levels with no sign of a threshold below which no association was evident. The effect estimate was also robust to the inclusion of co-occurring pollutants. We did not find significantly positive associations between NO2, BC or O3 and lung cancer incidence. Conclusions: Our results indicate that long-term ambient PM2.5 exposure may contribute to lung cancer incidence even at concentrations lower than current EU limit values and WHO Air Quality Guidelines.

Authors' response to: Qualitative job-exposure matrix--a tool for the quantification of population-attributable fractions for occupational lung carcinogens?

Telomere length is a biomarker reflective of aging and genomic instability. We previously found associations between longer measured leukocyte telomere length (LTL) and increased lung cancer risk in a pooled nested case-control study with 847 cases. Additionally, we reported that longer genetically-predicted telomere length (gTL) using a polygenic risk score (PRS) with 7 single nucleotide polymorphisms (SNPs) was associated with increased lung cancer risk among never-smoking Asian women. To investigate further, we conducted prospective cohort analyses of pre-diagnostic LTL and gTL in relation to risk of overall lung cancer and its subtypes in the UK Biobank. With over triple the number of cases, we had expanded statistical power to investigate lung cancer, adenocarcinoma (LUAD), and squamous cell carcinoma (SCC) among subgroups defined by smoking status and sex in this predominantly European study population. We analyzed 371,890 participants at baseline. Over the 12.36±1.64SD year follow-up, 2829 incident lung cancer cases were diagnosed, including 1078 LUAD and 487 SCC. LTL was measured using qPCR. Using European data, we calculated a weighted PRS for gTL. The PRS was derived from 130 linkage disequilibrium pruned SNPs (r2 > 0.01) associated with longer LTL in the UK Biobank. Multivariable Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of lung cancer in relation to log-transformed continuous and quartiles (Q) of LTL and gTL separately. Associations were estimated in the overall analytic sample and among smoking-sex subgroups. We conducted Mendelian Randomization (MR) analyses using MR-PRESSO with 130 genetic instruments to assess causal associations between LTL and lung cancer among Europeans.We found a strong dose-response relationship between longer LTL and increased lung cancer risk (p-trend= 2.6E-05), with the highest quartile being statistically significant (HRQ4vs.Q1=1.27, 95%CI: 1.15-1.42). The association was apparent for LUAD (p-trend=6.6E-10; HRQ4vs.Q1=1.78, 95%CI: 1.50-2.12), but not SCC. The lung cancer associations were prominent among never-smoking women (p-trend=4.0E-05) and never-smoking men (p-trend=2.0E-03). We also found dose-response relationships between longer gTL and risk of lung cancer (p-trend=4.2E-06) and LUAD (p-trend=2.1E-08). Additionally, we found evidence for causal associations between longer LTL and risk of lung cancer (HRper 1 SD gTL=1.87, 95%CI: 1.49-2.36, p=4.0E-07) and LUAD (HRper 1 SD gTL=2.45, 95%CI: 1.69-3.57, p=6.5E-06). Longer leukocyte telomere length potentially reflects biological processes relevant to the pathogenesis of lung cancer, particularly LUAD. Citation Format: Jason Yat-Yang Wong, Batel Blechter, Aubrey K. Hubbard, Jianxin Shi, Wei Hu, Mohammad Rahman, Shahinaz Gadalla, Mitchell Machiela, Nathaniel Rothman, Qing Lan. Measured and genetically-predicted leukocyte telomere length and lung cancer risk in the prospective UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3009.

This article is based on discussions of the lung cancer panel at the Hohenheim Consensus Meeting organized by the World Health Organization and the German Ministry of Health in November 1996. Panel members were international experts in the field of diet and cancer who discussed specific questions relating to lung cancer risk factors and prevention.

S01.07 The U19 Plans for Integration of Biomarkers Into Future Lung Cancer Screening

The authors investigated familial aggregation of lung cancer by means of a population-based case-control study, conducted in Germany between 1988 and 1993. They compared lung cancer prevalence in first degree relatives of 945 patients and 983 controls, accounting for various potential risk factors using logistic regression and generalized estimating equations. Some 83% of the study participants were male, and about 14% were below age 51 (young age group). Overall, lung cancer in parents or siblings was associated with a 1.67-fold (95% confidence interval (CI): 1.11, 2.52) increase in lung cancer risk. For the young participants, this risk was 4.75 (95% CI: 1.20, 18.77). Having multiple affected relatives (two or more) was related to a threefold risk elevation (odds ratio (OR) = 2.99, 95% CI: 0.32, 27.55). Paternal (OR = 1.64, 95% CI: 0.91, 2.96) but not maternal (OR = 0.91, 95% CI: 0.32, 2.61) lung cancer was associated with an increased risk of the disease. Lung cancer risk from smoking was particularly pronounced in the parents of cases (OR = 12.20, 95% CI: 3.34, 44.62 vs. OR = 7.93, 95% CI: 2.43, 25.91 in parents of controls). No risk elevation was detected for other smoking-related and other cancers in general. Results confirm previous findings and support the etiologic role of a genetic predisposition to lung cancer.

Introduction: Diabetes mellitus and lung cancer are two highly prevalent diseases on a global scale. The association between these two diseases has been the subject of study of many cohorts in the past, some of which presenting inconclusive results. Aim: To present existing evidence regarding the association of diabetes with lung cancer risk and survival as well as the impact of metformin and insulin on lung cancer. Methods: A narrative review of all the relevant published literature known to the authors was conducted. The references were identified by searching the Pubmed online database using the keywords such as diabetes and lung cancer risk, diabetes and lung cancer survival rates, metformin and lung cancer, insulin and lung cancer. Results : Although previous epidemiologic studies have failed to report any significant causal effect of diabetes on lung cancer risk, recent evidence from 2 large scale meta-analyses of observational studies and other studies showed a statistically significant correlation between nonsmoker diabetics and lung cancer risk (RR, 1.11; 95% CI, 1.02-1.20; I2 = 46.1% and RR, 1.14; 95% CI, 1.09-1.20; I2 = 0%). Recent evidence has shown that metformin is related to a lower risk of lung cancer incidence among never-smokers diabetic patients (HR, 0.57;95% CI, 0.33-0.99) and improved overall survival rates (HR=0.77, 95%CI=0.66-0.9, P=0.001) regardless of the histological type of lung cancer. On the other hand, a recently published large population-based retrospective cohort study has concluded that human insulin is associated with an increased risk of lung cancer (HR 1.545, 95% CI: 1.478-1.614). Interestingly, metformin has been reported to have an anti-resistant effect on lung cancer patients who are on Epidermal Growth Factor Receptor- Tyrosine Kinase Inhibitors, offering some protection against resistance to therapy. Conclusion: Published evidence shows that diabetes mellitus is associated with an increased risk of lung cancer and worse survival rates. Metformin plays a protective role in lung cancer pathogenesis and is also associated with prolonged progression-free survival in lung cancer patients with diabetes. There is a significant association between human insulin use and lung cancer risk. More randomized controlled studies are required to establish the positive association of diabetes and anti-diabetic drugs with lung cancer, taking into further consideration gender and lung cancer pathology as well as possible confounders such as smoking habits that can influence the results of these studies.

The majority of epidemiological studies investigating the relationship between physical activity (PA) and lung cancer risk support the role of recreational PA in lung cancer risk reduction. There have been fewer studies that have examined occupational PA in relation to lung cancer risk and inconclusive results have been reported with some evidence supporting a positive association. In most of these studies, the assessment of occupational PA was crude, based either on self-reported cross-sectional assessments or simple job title-based categorizations. Consideration of lifetime occupational PA and occupational PA accrued in different age windows may provide additional information regarding the direction and magnitude of the relationship, as well as the biologically relevant time window, between PA and lung cancer risk. Methods: The relationship between lifetime occupational PA and lung cancer risk was examined in a population-based case-control study of 1,136 incident lung cancer cases and 1,457 controls conducted in Montreal, Canada. Lifetime job history was collected via in-person interviews; for each job, the main tasks conducted were also obtained. The energy expenditure for each job-related task was determined via expert assessment by an industrial hygienist and an exercise physiologist in units of metabolic equivalent of task (MET). For each job, an average MET value was calculated by weighting the MET values of each job-related task by the hours per week spent in each task. The average lifetime occupational PA level was then computed by weighting the average MET value for each job by the duration spent in that job. The interview also elicited information on the subject's habitual recreational PA. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) with 95% confidence intervals (CI) for lung cancer risk associated with average lifetime occupational PA and average occupational PA levels in different age windows while controlling for potential confounders. Specifically, average occupational PA in the age windows of 18-24, 24-44 and 45-64 years in relation to lung cancer risk was examined. Confounding was assessed by combining directed acyclic graphs and the change-in-estimate procedure as a novel approach for covariate selection. Effect modification by smoking, body mass index (BMI) and exposure to occupational carcinogens was also assessed. All analyses were conducted separately for men and women. Results: The OR (95% CI) between average lifetime occupational PA and lung cancer risk, comparing the highest versus lowest quartile, was 1.38 (0.88-2.16) in men and 1.01 (0.58-1.76) in women. These associations were not modified by smoking level, BMI or occupational carcinogen exposure. Occupational PA in men was not associated with lung cancer in any of the age windows in which exposure was examined. In women, the highest versus lowest quartile of occupational PA was associated with an increased risk of lung cancer in the age window of 18-24 years (OR=1.72: 1.00-2.94); in the age windows of 24-44 (OR=0.89: 0.53-1.48) and 45-64 years (OR=0.63: 0.38-1.02) no increase in lung cancer risk was observed. When analyses were adjusted for recreational PA, results did not differ appreciably. Conclusion: These results fail to support the previously reported protective effects of PA on lung cancer risk. To the limited extent that they show a deviation from the null hypothesis of no influence on risk, they actually suggest some increased risk of lung cancer with higher occupational PA, although this relationship was inconsistent between sexes and in different age windows. This research was funded by the Canadian Cancer Society and the Guzzo-SRC Chair in Environment and Cancer. Citation Format: Vikki Ho, Marie-Élise Parent, Javier Pintos, Michal Abrahamowicz, Lise Gauvin, Jack Siemiatycki, Anita Koushik. Lifetime occupational physical activity and lung cancer risk in men and women. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A47.

Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. We applied a new job-exposure matrix (JEM) to translate lifetime work histories, collected by personal interview and coded into standard job titles, into never, low and high exposure levels for six known/suspected occupational lung carcinogens in the Environment and Genetics in Lung cancer Etiology (EAGLE) population-based case-control study, conducted in Lombardy region, Italy, in 2002-05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95% CI: 1.42-2.18), crystalline silica (OR: 1.31; 95% CI: 1.00-1.71) and nickel-chromium (OR: 1.18; 95% CI: 0.90-1.53); risk increased with exposure level. For polycyclic aromatic hydrocarbons, an increased risk (OR: 1.64; 95% CI: 0.99-2.70) was found only for high exposures. The PAFs for any exposure to asbestos, silica and nickel-chromium were 18.1, 5.7 and 7.0%, respectively, equivalent to an overall PAF of 22.5% (95% CI: 14.1-30.0). This corresponds to about 1016 (95% CI: 637-1355) male lung cancer cases/year in Lombardy. These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population.

To explore the association of -1195G > A genetic variant in the promoter region of cyclooxygenase 2 genetic (COX2) with the genetic susceptibility of lung cancer and its interaction with smoking. Totally, 956 lung cancer patients recruited between January 2000 and December 2008 at Cancer Hospital, Chinese Academy of Medical Science as the case group, and 994 frequency-matched controls were randomly selected from a pool of cancer-free subjects recruited from a nutritional survey. All subjects were ethnic Han Chinese. There was no sex, age restrictions. Case group and control group were matched. Informed consent was obtained and 2 ml peripheral blood was collected from each subject. All samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism method, smoking status of the subjects was surveyed.While the OR and 95% CI were estimated by logistic regression to evaluate the relation of COX2 -1195G > A variant and the risk of lung cancer. The genetic allele COX2 -1195AA of control group and case group were 24.9% (247/994) and 28.3% (271/956) . Case-control analysis showed an increased risk of developing lung cancer for -1195AA genotype carriers (OR = 1.36, 95% CI: 1.03-1.79), compared with -1195GG carriers. When stratified by smoking status, the significant increased risk of lung cancer was found among smokers with COX2-1195AA genotype, with the OR (95%CI) was 1.56 (1.08-2.25); while among non-smokers, difference of lung cancer risk was not found among different genotypes (OR = 1.17; 95%CI: 0.77-1.61). Among heavy smokers (pack-year >20), -1195AA and -1195AG genotype carriers have significant increased risk of lung cancer with 1.85 (1.16-2.95) and 1.62(1.08-2.43) of OR (95%CI), respectively; among light smokers (pack-year ≤ 20), the OR (95%CI) of lung cancer risk in -1195AG and -1195AA genotype carriers were 0.78 (0.47-1.30) and 1.08 (0.60-1.94), respectively. Genetic polymorphism in the promoter of COX2 gene interacting with smoking factor plays an important role in the development of lung cancer.

ED01.02 Tobacco Carcinogens and Lung Cancer Susceptibility