Abstract
Background
Observational studies showed associations between smoking, and airflow limitation, with lung squamous cell carcinoma (LUSC). However, the causal association of airflow limitation with LUSC and the modification by smoking status for the association remains unclear.
Methods
Genetic summary data were obtained from large genome-wide association studies (GWAS). One hundred two single nucleotide polymorphisms (SNPs) for airflow limitation (i.e., FEV1/FVC < 0.7) and 153 SNPs for smoking behavior were used as instrumental variables and the main MR analysis methods. The univariable and multivariable Mendelian Randomization (MR) in a two-sample setting were performed to assess the association of airflow limitation, and smoking behavior with LUSC.
Results
In the univariable MR analysis, genetic predisposition towards airflow limitation [Inverse Variance-Weighted (IVW) method Odds Ratio (OR) = 4.83, 95% Confidence Interval (CI) 1.55 to 15.06, P = 0.006], age of smoking initiation (IVW method OR = 0.10, 95%CI 0.02 to 0.36, P < 0.001), cigarettes smoked per day (IVW method OR = 3.10, 95%CI 2.07 to 4.63, P < 0.001), ex-smoking (IVW method OR = 0.47, 95%CI 0.31 to 0.69, P < 0.001), current smoking status (IVW method OR = 13.08, 95%CI 2.53 to 67.84, P = 0.002), pack-years of smoking (Weighted median method OR = 11.49, 95%CI 3.71 to 35.63, P < 0.001) were associated with LUSC. In the multivariable MR analysis, the causal effect of airflow limitation was still observed on LUSC (IVW method OR = 2.97, 95% CI 1.09 to 8.04, P = 0.032 adjusted for age of smoking initiation and cigarettes smoked per day; IVW method OR = 3.24, 95% CI 1.09 to 9.58, P = 0.033 adjusted for ex-smoking, current smoking status, and pack years of smoking; IVW method OR = 2.91, 95% CI 1.01 to 8.41, P = 0.049 adjusted for 5 smoking behaviors mentioned above).
Conclusions
Our MR analysis demonstrated that airflow limitation is likely to be an independent predictor of LUSC.
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Availability of data and material
The data sets generated and/or analyzed during the current study are publicly available. The corresponding websites and assessed dates were listed in the manuscripts and appendix.
References
Aït-Khaled N, Enarson DA, Ottmani S, El Sony A, Eltigani M, Sepulveda R (2007) Chronic airflow limitation in developing countries: burden and priorities. Int J Chron Obstruct Pulmon Dis 2(2):141–150
Bade BC, Dela Cruz CS (2020) Lung cancer 2020: epidemiology, etiology, and prevention. Clin Chest Med 41(1):1–24. https://doi.org/10.1016/j.ccm.2019.10.001
Barnes PJ (2016) Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 138(1):16–27. https://doi.org/10.1016/j.jaci.2016.05.011
Bozinovski S, Vlahos R, Anthony D, McQualter J, Anderson G, Irving L, Steinfort D (2016) COPD and squamous cell lung cancer: aberrant inflammation and immunity is the common link. Br J Pharmacol 173(4):635–648. https://doi.org/10.1111/bph.13198
Burgess S, Thompson SG (2015) Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol 181(4):251–260. https://doi.org/10.1093/aje/kwu283
Burgess S, Foley CN, Zuber V (2018) Inferring causal relationships between risk factors and outcomes from Genome-Wide Association Study Data. Annu Rev Genom Hum Genet 19:303–327. https://doi.org/10.1146/annurev-genom-083117-021731
Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, Theodoratou E (2019) Guidelines for performing Mendelian randomization investigations. Wellcome Open Res 4:186. https://doi.org/10.12688/wellcomeopenres.15555.2
Caramori G, Adcock IM, Casolari P, Ito K, Jazrawi E, Tsaprouni L, Papi A (2011) Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax 66(6):521–527. https://doi.org/10.1136/thx.2010.156448
Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK (2014) Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14(8):535–546. https://doi.org/10.1038/nrc3775
Dai X, Xie Y, Dong M (2022) Cancer-associated fibroblasts derived extracellular vesicles promote angiogenesis of colorectal adenocarcinoma cells through miR-135b-5p/FOXO1 axis. Cancer Biol Ther 23(1):76–88. https://doi.org/10.1080/15384047.2021.2017222
Davey Smith G, Holmes MV, Davies NM, Ebrahim S (2020) Mendel’s laws, Mendelian randomization and causal inference in observational data: substantive and nomenclatural issues. Eur J Epidemiol 35(2):99–111. https://doi.org/10.1007/s10654-020-00622-7
Fan YG, Jiang Y, Chang RS, Yao SX, Jin P, Wang W, Hu P (2011) Prior lung disease and lung cancer risk in an occupational-based cohort in Yunnan. China. Lung Cancer 72(2):258–263. https://doi.org/10.1016/j.lungcan.2011.01.032
Fry JS, Hamling JS, Lee PN (2012) Systematic review with meta-analysis of the epidemiological evidence relating FEV1 decline to lung cancer risk. BMC Cancer 12:498. https://doi.org/10.1186/1471-2407-12-498
Gandara DR, Hammerman PS, Sos ML, Lara PN Jr, Hirsch FR (2015) Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Clin Cancer Res 21(10):2236–2243. https://doi.org/10.1158/1078-0432.ccr-14-3039
Gerald LB, Bailey WC (2002) Global initiative for chronic obstructive lung disease. J Cardiopulm Rehabil 22(4):234–244. https://doi.org/10.1097/00008483-200207000-00004
Grahn K, Gustavsson P, Andersson T, Lindén A, Hemmingsson T, Selander J, Wiebert P (2021) Occupational exposure to particles and increased risk of developing chronic obstructive pulmonary disease (COPD): A population-based cohort study in Stockholm Sweden. Environ Res 200:111739. https://doi.org/10.1016/j.envres.2021.111739
Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, Haycock PC (2018) The MR-Base platform supports systematic causal inference across the human phenome. Elife. https://doi.org/10.7554/eLife.34408
Hogg JC (2004) Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364(9435):709–721. https://doi.org/10.1016/s0140-6736(04)16900-6
Kachuri L, Johansson M, Rashkin SR, Graff RE, Bossé Y, Manem V, Hung RJ (2020) Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility. Nat Commun 11(1):27. https://doi.org/10.1038/s41467-019-13855-2
Kryston TB, Georgiev AB, Pissis P, Georgakilas AG (2011) Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res 711(1–2):193–201. https://doi.org/10.1016/j.mrfmmm.2010.12.016
Langen RC, Korn SH, Wouters EF (2003) ROS in the local and systemic pathogenesis of COPD. Free Radic Biol Med 35(3):226–235. https://doi.org/10.1016/s0891-5849(03)00316-2
Liu M, Jiang Y, Wedow R, Li Y, Brazel DM, Chen F, Vrieze S (2019) Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet 51(2):237–244. https://doi.org/10.1038/s41588-018-0307-5
Nakanishi T, Cerani A, Forgetta V, Zhou S, Allen RJ, Leavy OC, Richards JB (2022) Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study. Eur Respir J 59(2):2003979. https://doi.org/10.1183/13993003.03979-2020
Ngkelo A, Meja K, Yeadon M, Adcock I, Kirkham PA (2012) LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling. J Inflamm (Lond) 9(1):1. https://doi.org/10.1186/1476-9255-9-1
Oelsner EC, Carr JJ, Enright PL, Hoffman EA, Folsom AR, Kawut SM, Barr RG (2016) Per cent emphysema is associated with respiratory and lung cancer mortality in the general population: a cohort study. Thorax 71(7):624–632. https://doi.org/10.1136/thoraxjnl-2015-207822
Salvi SS, Barnes PJ (2009) Chronic obstructive pulmonary disease in non-smokers. Lancet 374(9691):733–743. https://doi.org/10.1016/s0140-6736(09)61303-9
Sanderson E, Davey Smith G, Windmeijer F, Bowden J (2019) An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol 48(3):713–727. https://doi.org/10.1093/ije/dyy262
Sandri BJ, Masvidal L, Murie C, Bartish M, Avdulov S, Higgins L, Larsson O (2019) Distinct cancer-promoting stromal gene expression depending on lung function. Am J Respir Crit Care Med 200(3):348–358. https://doi.org/10.1164/rccm.201801-0080OC
Schwartz AG, Ruckdeschel JC (2006) Familial lung cancer: genetic susceptibility and relationship to chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173(1):16–22. https://doi.org/10.1164/rccm.200502-235PP
Sobue T, Yamamoto S, Hara M, Sasazuki S, Sasaki S, Tsugane S (2002) Cigarette smoking and subsequent risk of lung cancer by histologic type in middle-aged Japanese men and women: the JPHC study. Int J Cancer 99(2):245–251. https://doi.org/10.1002/ijc.10308
Takiguchi Y, Sekine I, Iwasawa S, Kurimoto R, Tatsumi K (2014) Chronic obstructive pulmonary disease as a risk factor for lung cancer. World J Clin Oncol 5(4):660–666. https://doi.org/10.5306/wjco.v5.i4.660
Wang H, Yang L, Zou L, Huang D, Guo Y, Pan M, Lu J (2012) Association between chronic obstructive pulmonary disease and lung cancer: a case-control study in Southern Chinese and a meta-analysis. PLoS ONE 7(9):e46144. https://doi.org/10.1371/journal.pone.0046144
Wang C, Xu J, Yang L, Xu Y, Zhang X, Bai C, He J (2018a) Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study. Lancet 391(10131):1706–1717. https://doi.org/10.1016/s0140-6736(18)30841-9
Wang W, Xie M, Dou S, Cui L, Zheng C, Xiao W (2018b) The link between chronic obstructive pulmonary disease phenotypes and histological subtypes of lung cancer: a case-control study. Int J Chron Obstruct Pulmon Dis 13:1167–1175. https://doi.org/10.2147/copd.s158818
Wilson DO, Weissfeld JL, Balkan A, Schragin JG, Fuhrman CR, Fisher SN, Sciurba FC (2008) Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med 178(7):738–744. https://doi.org/10.1164/rccm.200803-435OC
Yang IA, Holloway JW, Fong KM (2013) Genetic susceptibility to lung cancer and co-morbidities. J Thorac Dis 5(5):S454-462. https://doi.org/10.3978/j.issn.2072-1439.2013.08.06
Zhang X, Jiang N, Wang L, Liu H, He R (2017) Chronic obstructive pulmonary disease and risk of lung cancer: a meta-analysis of prospective cohort studies. Oncotarget 8(44):78044–78056. https://doi.org/10.18632/oncotarget.20351
Zheng J, Baird D, Borges MC, Bowden J, Hemani G, Haycock P, Smith GD (2017) Recent developments in mendelian randomization studies. Curr Epidemiol Rep 4(4):330–345. https://doi.org/10.1007/s40471-017-0128-6
Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Liang X (2019) Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 394(10204):1145–1158. https://doi.org/10.1016/s0140-6736(19)30427-1
Acknowledgements
This work was supported by several fundings. However, study fundings had no influence on this study. Thanks to Dr. Zihui Wang and Dr. Yi Feng for their support of the methodology.
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Conceptualization QZ, YC. Data curation QZ, GC, and FC. Formal analysis QZ, GC. Funding acquisition YC, HL and FC. Investigation: QZ, and GC. Methodology QZ, GC, HL and FC. Project administration QZ, YC, GC, FC, WG, HL, LG and ML. Resources QZ, GC and WG. Software: ZW, QZ, GC. Supervision YC. Validation QZ, GC, and FC. Visualization GC, LG and FC. Writing-original draft All authors. Writing-review & editing All authors.
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Zhang, Q., Cai, G., Cui, F. et al. The relationship of airflow limitation with lung squamous cell carcinoma: evidence from mendelian randomization analysis. J Cancer Res Clin Oncol 149, 6999–7006 (2023). https://doi.org/10.1007/s00432-023-04612-6
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DOI: https://doi.org/10.1007/s00432-023-04612-6