Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors
© Brenner et al; licensee BioMed Central Ltd. 2010
Received: 26 November 2009
Accepted: 14 June 2010
Published: 14 June 2010
We 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.
445 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.
Any 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.
Occupational exposures and family history of cancer with young onset were important risk factors among never smokers.
Lung cancer is the most common type of cancer and the leading cause of cancer death in Canada with approximately 23,400 new cases (14.3 percent of all new cancers among males, 13.1 percent among females) and 20,500 deaths annually . Although active tobacco smoking has been well established as the major cause of lung cancer [2–5], the etiology among never smokers beyond ETS exposure  remains to be elucidated and is of great public health importance [7, 8]. The influences of indoor air pollution, workplace exposures and previous history of respiratory disease on lung cancer development among never smokers require additional investigation.
To further understand the etiology of lung cancer, with special consideration given to never smokers, we conducted a case-control study in the greater Toronto area with oversampling among never smokers. The objective of this study was to evaluate potential lung cancer risk factors including ETS exposure, family history of cancer, indoor air pollution, workplace exposures and history of previous respiratory diseases.
Study population and data collection
The case series consisted of incident cases of cancer of the trachea, bronchus or lung diagnosed among men and women between the ages of 20 and 84. Cases were identified between 1997 and 2002 through four major tertiary care hospitals in metropolitan Toronto that have the largest lung cancer services for surgical and medical oncology, including the two centres that see all patients who require radiotherapy. Diagnoses were histologically confirmed by a pulmonary pathologist following classification according to the ICD for oncology-3 . As one of the main objectives of the study was to study lung cancer etiology other than from tobacco exposure, among never smokers, we therefore over sampled never smoking lung cancer patients, leading to 35% of the total cases being never smokers. A total of 445 eligible cases and 948 controls were recruited into the study for whom consent was obtained. Controls were residents of metropolitan Toronto who did not have cancer at the time of recruitment. Population-based controls were randomly sampled from property tax assessment files (n = 425). Hospital-based controls were sampled from patients seen in the Mount Sinai Hospital Family Medicine Clinic (n = 523), which is a non-specialty, family medicine practice situated within the hospital where recruitment into the study was conducted independent of reason for visit to the clinic. Controls were frequency matched with cases on sex and ethnicity. Participation rates were similar between cases (62%, 445 of 716 total eligible, 116 refused participation, whereas the remaining patients died before study entry and/or complete data collection was possible) and population controls, (60%, 425 of total 718 eligible) and slightly higher among hospital controls (84%, 523 of 621 total eligible). Informed consent was obtained from all participants and approvals were obtained from the Research Ethics Board.
Participants' lifetime information concerning tobacco consumption, exposure to ETS exposure, air pollution from heating, workplace exposures to potential lung carcinogens, family history of cancer and health history were collected through a detailed questionnaire administered via interview either in person or over the telephone. 'Never smokers' were defined as those who had not smoked more than 100 cigarettes in their lifetime. 'Former smokers' were smokers who had stopped smoking for at least two years at the date of the interview. Cumulative tobacco exposure was estimated in pack-years, where a pack is 20 cigarette equivalents.
Environmental tobacco smoke (ETS) exposure was categorized as having been exposed to second hand smoke either during childhood, as an adult or at work, with duration in years categorized to examine dose-response relationships. Indoor air pollution from heating was collected for oil, gas, coal & wood sources, with the duration of each exposure recorded. A measure of solid fuels for heating (coal and wood) was also created to examine the potential for differential effects of heating sources with particulate matter emission. Workplace exposures to potential lung carcinogens including asbestos, paints and/or solvents, welding equipment, pesticides, grain elevator dust, wood dust and smoke, soot or exhaust (not from tobacco) were dichotomized as exposed or unexposed. Family history was classified as the number of first degree relatives with any cancer, lung cancer, or aerodigestive tract cancers with distinction by relative types.
Differences in demographics between cases and controls as well as between control types were evaluated using χ2 tests and t-tests. Multivariate unconditional logistic regression models were used to obtain odds ratio (OR) estimates and 95% confidence intervals (CI) for the associations between exposures and lung cancer risk, adjusted for cumulative tobacco exposures (pack-years), age (years), gender, education and ethnicity. Given that cases were sampled based on smoking status, all analyses were adjusted for smoking and the focus of this investigation is on factors other than tobacco. Indicator variables were created for all categorical variables in analyses. We stratified analyses by years of exposure and age of onset when applicable in an attempt to determine the temporality of potential exposure-disease associations. Analyses were conducted using SAS Version 9.1 (SAS V9.1; SAS Institute Inc, Cary NC, USA).
We also applied the Spitz (2007)  and Liverpool Lung Project (2008)  lung cancer risk models to evaluate the predictive ability of their models within our population. We stratified our population by smoking status to examine the area under the curve and Hosmer Lemeshow goodness-of-fit statistics  within the subgroups. Previous history of hay fever and dust exposure were not available in our study and were thus not included as part of the Spitz model.
Demographic characteristics of lung cancer patients and controls in a population based case-control study, Greater Toronto Area, Ontario, 1997- 2002
p = 0.03
1 (< 1)
Age, Mean ± SD
66 ± 10
59 ± 13
64 ± 12
56 ± 16
53 ± 17
54 ± 16
p = 0.07
< 8 years
All types of smoking combined
Former (> 2 yrs. Since quitting)
Pack-yearsb, Mean ± SD
45 ± 35
25 ± 27
Squamous cell carcinoma
Large cell carcinoma
The association between ETS and risk of lung cancer among never smokers in a population based case-control study, Greater Toronto Area, Ontario, 1997-2002
Total Population n = 1393
Never smokers n = 622
At home Adult and/or Child
< 10 years
> 10 years
At both home and work
The association between workplace exposures and risk of lung cancer in a population based case-control study, Greater Toronto Area, Ontario, 1997-2002
Total Population n = 1393
Never smokers n = 622
No previous exposures
Any occupational exposure
Ever worked with/been exposed to:
Solvents, paints or thinners
Grain elevator dust
smoke-soot or exhaust
other than tobacco
The association between previous medical history and risk of lung cancer in a population based case-control study, Greater Toronto Area, Ontario, 1997-2002
Total Population n = 1393
Never smokers n = 622
Other respiratory illness
The association between family history of previous cancer and risk of lung cancer in a population based case-control study, Greater Toronto Area, Ontario, 1997-2002
Total Population n = 1393
Never smokers n = 622
No family history of any cancer
Positive family history of any cancer
2 or more
Affected relatives age at onset < 50
Positive family history of aero-digestive cancer
Positive family history of lung cancer
Applying the Spitz risk model indicated that there was only modest predictive ability among never smokers in our population (Area under the Curve (AUC) 0.525). Among smokers (current and former), however, the Spitz model was shown to have better predictive power, (AUC former smokers = 0.716, current smokers = 0.780), despite our study not possessing data for hay fever or dust exposure. The Liverpool Lung Project risk model provided similar outcomes in prediction, identifying cases in the total population well (AUC 0.788) with lower statistics when applied to only never smokers in the population (AUC 0.721).
In this study we investigated the impact of several factors on lung cancer risk overall as well as specifically among never smokers. The most important risk factors we observed among never smokers were exposure to potential occupational carcinogens, family history of cancer with young onset and previous history of respiratory diseases among the total population.
In our examination of the effects of several occupational exposures among never smokers in the greater Toronto area we found several significant potential sources of increased risk including exposure to solvents, paints or thinners, welding equipment and smoke, soot or exhaust (from sources other than tobacco). This information is important as data concerning occupational exposures and lung cancer among never smokers are still lacking in the literature .
Our results support the concept that exposure to exhaust fumes and or soot/smoke (from non-tobacco sources) is a source of carcinogenic exposure. A previous meta-analysis suggested that when adjusted for smoking, heavy diesel exhaust exposure was associated with an increased risk (OR 1.4, 95% CI 1.3-1.6) , and a recent study examining the effects in a similar Canadian population, was also suggestive of increased risk (OR 1.6, 95% CI 0.9-2.8) . With regards to soot and exhaust exposure, these substances contain benzo[a]pyrene, a known carcinogen, and has been consistently shown to increase risk [16, 17]. We observed an increased risk associated with exposure to paints, thinners and solvents, which was in agreement with previous studies [18–22]. When ingested, these substances can affect the pleural membranes, causing scarring and or mutations, thus increasing the potential for carcinogenesis . Similarly, exposure to welding equipment was associated with increased risk as observed in a meta-analysis of welding and lung cancer . Wood dust is a known carcinogen associated with the development of cancers of the respiratory tract [25–27]. In this study the estimate for wood dust exposure was suggestive of increased risk among never smokers. While these observations require replication, they are consistent with the overall patterns seen for wood dust, with the potential implication that workplace exposures should be controlled and monitored. Asbestos exposure has been previously shown to have an effect on lung cancer risk [28, 29]; however, no association between lung cancer and asbestos was seen here among never smokers, contrary to previously published results . The discrepancies with the previous studies may be due to an attenuation of the risk estimate as a result of the simple dichotomy used to indicate asbestos exposure which may not distinguish between actual or potential exposure among the small number of individuals reporting exposure in this non-occupational cohort. Overall, these observations provide support for efforts to control, monitor and reduce exposures to potentially hazardous workplace exposures, which in this study are shown to be associated with lung cancer, even among never smokers.
Our findings are consistent with the evidence suggesting that a previous history of acquired respiratory conditions is a risk factor for lung cancer [31–41]. Chronic inflammation and airway obstruction may predispose individuals to various types of cancer as the damage created by acquired pulmonary diseases such as chronic obstructive pulmonary disease (COPD) may be involved in cancer development [42–47]. Proposed biological mechanisms include enhanced effects of carcinogenic exposures in the presence of chronic inflammation or a compromised immune response [48, 49], as well as the possibility of lung cancer evolving directly from the scar lesions created by non-malignant conditions [50, 51]. Although the analyses performed here accounted for active smoking, it is still possible that the relationship between acquired respiratory disease and lung cancer is partially explained by residual confounding from tobacco . In addition, due to the relatively small numbers further investigations among never smokers is still warranted. Further elucidation and characterization of the genetic variants associated with inflammation of the lungs may also help to clarify the role of acquired respiratory conditions in the etiology of lung cancer.
ETS exposure was not found to significantly increase risk among never smokers in this study, however, several potential explanations are possible. ETS exposure either as a child or an adult in the home or the workplace has been evaluated in numerous studies . The results, however, have been inconsistent as to the significance and magnitude of the effects among never smokers. When estimates were pooled in a meta-analysis of 34 case-control studies of non-smokers, a pooled relative risk of 1.2 (95% CI 1.1-1.4) was observed, although only seven out of 34 studies reporting significantly elevated risk . It was suggested that the inconsistency in the significance of findings across studies could be due to issues of sample size, measurement error, recall bias and confounding . Despite our efforts to minimize misclassification bias by collecting data on involuntary tobacco smoke exposure data for home, work and other exposure locations during both childhood and adulthood, the possibility of these issues cannot be excluded. The main limitation in our study is the lack of power to detect a modest effect. Non-differential misclassification of the dichotomous exposures may also lead to a bias toward to null. We combined hospital and population based controls in an attempt to increase our sample size and in turn the ability to detect significant associations. In order to address any issues created by this pooling we investigated effect estimates among only population based controls. Effect estimates were of a similar magnitude and no significant associations were observed among population based controls that were not observed among the total population.
Another limitation of this study is its dependence on self-reported exposures. Previous history of respiratory disease was self-reported as access to patient medical records was not available for validation, and similarly, validation of occupation was not possible due to a lack of occupational records. Even so, this study provides risk estimates for a relatively large group of never smoking lung cancer cases in a population-based study, and thus yields findings that are of increasing relevance given recent changes in tobacco use in the population. The detailed risk factor information concerning indoor air pollution and family history collected from patients following diagnosis, as well as similar participation rates among cases and controls are additional strengths of the study.
When applying previously specified risk prediction models to our population, both models were able to adequately predict outcomes among smokers, however, both models had substantially less predictive ability among never smokers. This indicates that previously identified risk prediction models have little utility among never smokers and that additional determinants of increased risk or susceptibility must still be identified among this group. Identification of these new factors among never smokers has been difficult due to the small numbers of never smoking cases in studies to date. With the development of large-scale collaborations and consortia , it will become possible for much more detailed risk models to be evaluated among larger populations of never smokers, leading ultimately to improved risk prediction and understanding of lung cancer etiology among never smokers.
This study mainly assessed environmental risk factors for the development of lung cancer in never smokers. It is now clear that the molecular pathogenesis of lung cancer in smokers and non-smokers is different, with a higher proportion of adenocarincoma observed among never smoking cases. Recent studies have demonstrated that activating mutations in the EGFR tyrosine kinase domain occur much more frequently in lung cancers in non and never smoking patients. Furthermore, these mutations are found significantly more often in adenocarcinomas, women, and individuals of Asian origin where the mutation rate can reach 60% in patients with these characteristics . These characteristics were all significantly higher in our never smoking subset. Unfortunately, we do not have adequate tissue samples to assess mutation status in our cases, but studies of the interaction between EGFR mutations and environmental factors deserve further investigation.
In conclusion, occupational exposures displayed the strongest associations with increased lung cancer risk among never smokers in this study. Further understanding of the role of these factors in lung cancer etiology may ultimately lead to improved lung cancer prevention strategies for the whole population.
The authors gratefully acknowledge the collaboration of Drs. A. Bezjak, R. Burke, G. Darling, R. Feld, A. Gordon, D. Jones, D. Payne, J. Ringash, T. Rohan, E. Spratt, R. Tyndale, D. Vespirini, Y. Ung; the support of Mount Sinai Hospital, Princess Margaret Hospital, Sunnybrook & Women's College Health Sciences Centre, St. Joseph's Hospital, the University Health Network, and the Yee Hong Medical Centre; and the assistance of T. Chan, I. Fan, M. Kebabdjian, G. Manca, C. Neglia, T. Oh, S. Farooq, K. Scott, N. Sheikh, A. Vasilopoulos, E. Weinroth, H. White and K. Yoong. This work was funded through a grant from the National Cancer Institute of Canada with funds from the Canadian Cancer Society (NCIC # 8046); JRM was supported as an Investigator of the Canadian Institute for Health Research.
The study was also supported by a Canadian Cancer Society Research Institute grant (no. 020214). DB holds a CIHR Canada Graduate Scholarship.
- Canadian Cancer Society's Steering Committee: Canadian Cancer Statistics 2009. 2009, Toronto: Canadian Cancer SocietyGoogle Scholar
- Daff ME, Doll R, Kennaway EL: Cancer of the lung in relation to tobacco. Br J Cancer. 1951, 5 (1): 1-20.View ArticlePubMedPubMed CentralGoogle Scholar
- Doll R, Peto R, Wheatley K, Gray R, Sutherland I: Mortality in relation to smoking: 40 years' observations on male British doctors. Bmj. 1994, 309 (6959): 901-911.View ArticlePubMedPubMed CentralGoogle Scholar
- Tobacco Smoke and Involuntary Smoking. 2004, Lyon, France: IARC Press, 83:Google Scholar
- Baron J, Rohan TE: Tobacco. Cancer epidemiology and Prevention. Edited by: Schottenfeld D, Fraumeni JF. 1996, New York, NY: Oxford University Press, 2Google Scholar
- Hackshaw AK, Law MR, Wald NJ: The accumulated evidence on lung cancer and environmental tobacco smoke. Bmj. 1997, 315 (7114): 980-988.View ArticlePubMedPubMed CentralGoogle Scholar
- Subramanian J, Govindan R: Lung cancer in never smokers: a review. J Clin Oncol. 2007, 25 (5): 561-570. 10.1200/JCO.2006.06.8015.View ArticlePubMedGoogle Scholar
- Sun S, Schiller JH, Gazdar AF: Lung cancer in never smokers--a different disease. Nat Rev Cancer. 2007, 7 (10): 778-790. 10.1038/nrc2190.View ArticlePubMedGoogle Scholar
- World Health Organization: International Classification of Diseases for Oncology - 3. 2000, Geneva, WHOGoogle Scholar
- Spitz MR, Hong WK, Amos CI, Wu X, Schabath MB, Dong Q, Shete S, Etzel CJ: A risk model for prediction of lung cancer. J Natl Cancer Inst. 2007, 99 (9): 715-726. 10.1093/jnci/djk153.View ArticlePubMedGoogle Scholar
- Cassidy A, Myles JP, van Tongeren M, Page RD, Liloglou T, Duffy SW, Field JK: The LLP risk model: an individual risk prediction model for lung cancer. Br J Cancer. 2008, 98 (2): 270-276. 10.1038/sj.bjc.6604158.View ArticlePubMedGoogle Scholar
- Lemeshow S, Hosmer DW: A review of goodness of fit statistics for use in the development of logistic regression models. Am J Epidemiol. 1982, 115 (1): 92-106.PubMedGoogle Scholar
- Neuberger JS, Field RW: Occupation and lung cancer in nonsmokers. Rev Environ Health. 2003, 18 (4): 251-267.View ArticlePubMedGoogle Scholar
- Lipsett M, Campleman S: Occupational exposure to diesel exhaust and lung cancer: a meta-analysis. Am J Public Health. 1999, 89 (7): 1009-1017. 10.2105/AJPH.89.7.1009.View ArticlePubMedPubMed CentralGoogle Scholar
- Parent ME, Rousseau MC, Boffetta P, Cohen A, Siemiatycki J: Exposure to diesel and gasoline engine emissions and the risk of lung cancer. Am J Epidemiol. 2007, 165 (1): 53-62. 10.1093/aje/kwj343.View ArticlePubMedGoogle Scholar
- Lloyd JW: Long-term mortality study of steelworkers. V. Respiratory cancer in coke plant workers. J Occup Med. 1971, 13 (2): 53-68. 10.1097/00043764-197102000-00001.View ArticlePubMedGoogle Scholar
- Doll R, Fisher RE, Gammon EJ, Gunn W, Hughes GO, Tyrer FH, Wilson W: Mortality of Gasworkers with Special Reference to Cancers of the Lung and Bladder, Chronic Bronchitis, and Pneumoconiosis. Br J Ind Med. 1965, 22: 1-12.PubMedPubMed CentralGoogle Scholar
- Zeka A, Mannetje A, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Navratilova M, et al: Lung cancer and occupation in nonsmokers: a multicenter case-control study in Europe. Epidemiology. 2006, 17 (6): 615-623. 10.1097/01.ede.0000239582.92495.b5.View ArticlePubMedGoogle Scholar
- Stockwell HG, Matanoski GM: A case-control study of lung cancer in painters. J Occup Med. 1985, 27 (2): 125-126.PubMedGoogle Scholar
- Lerchen ML, Wiggins CL, Samet JM: Lung cancer and occupation in New Mexico. J Natl Cancer Inst. 1987, 79 (4): 639-645.PubMedGoogle Scholar
- Muscat JE, Stellman SD, Richie JP, Wynder EL: Lung cancer risk and workplace exposures in black men and women. Environ Res. 1998, 76 (2): 78-84. 10.1006/enrs.1997.3787.View ArticlePubMedGoogle Scholar
- Chen R, Seaton A: A meta-analysis of painting exposure and cancer mortality. Cancer Detect Prev. 1998, 22 (6): 533-539. 10.1046/j.1525-1500.1998.00A47.x.View ArticlePubMedGoogle Scholar
- IARC Monographs programme on the evaluation of the carcinogenic risk of chemicals to humans. Preamble. IARC Monogr Eval Carcinog Risk Chem Hum. 1986, 39: 13-32.Google Scholar
- Ambroise D, Wild P, Moulin JJ: Update of a meta-analysis on lung cancer and welding. Scand J Work Environ Health. 2006, 32 (1): 22-31.View ArticlePubMedGoogle Scholar
- Jayaprakash V, Natarajan KK, Moysich KB, Rigual NR, Ramnath N, Natarajan N, Reid ME: Wood Dust Exposure and the Risk of Upper Aero-Digestive and Respiratory Cancers in Males. Occup Environ Med. 2008, 65 (10): 647-54. 10.1136/oem.2007.036210.View ArticlePubMedGoogle Scholar
- Baran S, Teul I: Wood dust: an occupational hazard which increases the risk of respiratory disease. J Physiol Pharmacol. 2007, 58 (Suppl 5 Pt 1): 43-50.PubMedGoogle Scholar
- Barcenas CH, Delclos GL, El-Zein R, Tortolero-Luna G, Whitehead LW, Spitz MR: Wood dust exposure and the association with lung cancer risk. Am J Ind Med. 2005, 47 (4): 349-357. 10.1002/ajim.20137.View ArticlePubMedGoogle Scholar
- Hillerdal G, Henderson DW: Asbestos, asbestosis, pleural plaques and lung cancer. Scand J Work Environ Health. 1997, 23 (2): 93-103.View ArticlePubMedGoogle Scholar
- Gustavsson P, Nyberg F, Pershagen G, Scheele P, Jakobsson R, Plato N: Low-dose exposure to asbestos and lung cancer: dose-response relations and interaction with smoking in a population-based case-referent study in Stockholm, Sweden. Am J Epidemiol. 2002, 155 (11): 1016-1022. 10.1093/aje/155.11.1016.View ArticlePubMedGoogle Scholar
- Neuberger JS, Mahnken JD, Mayo MS, Field RW: Risk factors for lung cancer in Iowa women: implications for prevention. Cancer Detect Prev. 2006, 30 (2): 158-167. 10.1016/j.cdp.2006.03.001.View ArticlePubMedPubMed CentralGoogle Scholar
- Skillrud DM, Offord KP, Miller RD: Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med. 1986, 105 (4): 503-507.View ArticlePubMedGoogle Scholar
- Mayne ST, Buenconsejo J, Janerich DT: Previous lung disease and risk of lung cancer among men and women nonsmokers. Am J Epidemiol. 1999, 149 (1): 13-20.View ArticlePubMedGoogle Scholar
- Samet JM, Humble CG, Pathak DR: Personal and family history of respiratory disease and lung cancer risk. Am Rev Respir Dis. 1986, 134 (3): 466-470.PubMedGoogle Scholar
- Alavanja MC, Brownson RC, Boice JD, Hock E: Preexisting lung disease and lung cancer among nonsmoking women. Am J Epidemiol. 1992, 136 (6): 623-632.PubMedGoogle Scholar
- Brenner AV, Wang Z, Kleinerman RA, Wang L, Zhang S, Metayer C, Chen K, Lei S, Cui H, Lubin JH: Previous pulmonary diseases and risk of lung cancer in Gansu Province, China. Int J Epidemiol. 2001, 30 (1): 118-124. 10.1093/ije/30.1.118.View ArticlePubMedGoogle Scholar
- Wu AH, Fontham ET, Reynolds P, Greenberg RS, Buffler P, Liff J, Boyd P, Henderson BE, Correa P: Previous lung disease and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol. 1995, 141 (11): 1023-1032.PubMedGoogle Scholar
- Talbot-Smith A, Fritschi L, Divitini ML, Mallon DF, Knuiman MW: Allergy, atopy, and cancer: a prospective study of the 1981 Busselton cohort. Am J Epidemiol. 2003, 157 (7): 606-612. 10.1093/aje/kwg020.View ArticlePubMedGoogle Scholar
- Osann KE, Lowery JT, Schell MJ: Small cell lung cancer in women: risk associated with smoking, prior respiratory disease, and occupation. Lung Cancer. 2000, 28 (1): 1-10. 10.1016/S0169-5002(99)00106-3.View ArticlePubMedGoogle Scholar
- Santillan AA, Camargo CA, Colditz GA: A meta-analysis of asthma and risk of lung cancer (United States). Cancer Causes Control. 2003, 14 (4): 327-334. 10.1023/A:1023982402137.View ArticlePubMedGoogle Scholar
- Boffett P, Ye W, Boman Nyren: Lung cancer risk in a population-based cohort of patients hospitalized for asthma in Sweden. Eur Respir J. 2002, 19 (1): 127-133. 10.1183/09031936.02.00245802.View ArticleGoogle Scholar
- Ramanakumar AV, Parent ME, Menzies D, Siemiatycki J: Risk of lung cancer following nonmalignant respiratory conditions: evidence from two case-control studies in Montreal, Canada. Lung Cancer. 2006, 53 (1): 5-12. 10.1016/j.lungcan.2006.04.007.View ArticlePubMedGoogle Scholar
- O'Byrne KJ, Dalgleish AG: Chronic immune activation and inflammation as the cause of malignancy. Br J Cancer. 2001, 85 (4): 473-483. 10.1054/bjoc.2001.1943.View ArticlePubMedPubMed CentralGoogle Scholar
- Seow A, Ng DP, Choo S, Eng P, Poh WT, Ming T, Wang YT: Joint effect of asthma/atopy and an IL-6 gene polymorphism on lung cancer risk among lifetime non-smoking Chinese women. Carcinogenesis. 2006, 27 (6): 1240-1244. 10.1093/carcin/bgi309.View ArticlePubMedGoogle Scholar
- Bauer AK, Malkinson AM, Kleeberger SR: Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities. Am J Physiol Lung Cell Mol Physiol. 2004, 287 (4): L685-703. 10.1152/ajplung.00223.2003.View ArticlePubMedGoogle Scholar
- Schabath MB, Delclos GL, Martynowicz MM, Greisinger AJ, Lu C, Wu X, Spitz MR: Opposing effects of emphysema, hay fever, and select genetic variants on lung cancer risk. Am J Epidemiol. 2005, 161 (5): 412-422. 10.1093/aje/kwi063.View ArticlePubMedGoogle Scholar
- Suzuki K, Ito Y, Wakai K, Kawado M, Hashimoto S, Seki N, Ando M, Nishino Y, Kondo T, Watanabe Y, et al: Serum heat shock protein 70 levels and lung cancer risk: a case-control study nested in a large cohort study. Cancer Epidemiol Biomarkers Prev. 2006, 15 (9): 1733-1737. 10.1158/1055-9965.EPI-06-0005.View ArticlePubMedGoogle Scholar
- Yang P, Wentzlaff KA, Katzmann JA, Marks RS, Allen MS, Lesnick TG, Lindor NM, Myers JL, Wiegert E, Midthun DE, et al: Alpha1-antitrypsin deficiency allele carriers among lung cancer patients. Cancer Epidemiol Biomarkers Prev. 1999, 8 (5): 461-465.PubMedGoogle Scholar
- Ohshima H, Bartsch H: Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res. 1994, 305 (2): 253-264.View ArticlePubMedGoogle Scholar
- Zheng W, Blot WJ, Liao ML, Wang ZX, Levin LI, Zhao JJ, Fraumeni JF, Gao YT: Lung cancer and prior tuberculosis infection in Shanghai. Br J Cancer. 1987, 56 (4): 501-504.View ArticlePubMedPubMed CentralGoogle Scholar
- Madri JA, Carter D: Scar cancers of the lung: origin and significance. Hum Pathol. 1984, 15 (7): 625-631. 10.1016/S0046-8177(84)80286-5.View ArticlePubMedGoogle Scholar
- Xie L, Ugnat AM, Morriss J, Semenciw R, Mao Y: Histology-related variation in the treatment and survival of patients with lung carcinoma in Canada. Lung Cancer. 2003, 42 (2): 127-139. 10.1016/S0169-5002(03)00283-6.View ArticlePubMedGoogle Scholar
- Boffetta P, Ye W, Boman Nyren: Lung cancer risk in a population-based cohort of patients hospitalized for asthma in Sweden. Eur Respir J. 2002, 19 (1): 127-133. 10.1183/09031936.02.00245802.View ArticlePubMedGoogle Scholar
- Boffetta P: Involuntary smoking and lung cancer. Scand J Work Environ Health. 2002, 28 (Suppl 2): 30-40.PubMedGoogle Scholar
- Lee PN: Difficulties in assessing the relationship between passive smoking and lung cancer. Stat Methods Med Res. 1998, 7 (2): 137-163. 10.1191/096228098669795194.View ArticlePubMedGoogle Scholar
- Hung RJ, Christiani DC, Risch A, Popanda O, Haugen A, Zienolddiny S, Benhamou S, Bouchardy C, Lan Q, Spitz MR, et al: International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways. Cancer Epidemiol Biomarkers Prev. 2008, 17 (11): 3081-3089. 10.1158/1055-9965.EPI-08-0411.View ArticlePubMedPubMed CentralGoogle Scholar
- Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009, 361 (10): 947-957. 10.1056/NEJMoa0810699.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/285/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.