Tumor Biology

, Volume 35, Issue 3, pp 2777–2785 | Cite as

Quantitative assessment of the influence of common variations (rs8034191 and rs1051730) at 15q25 and lung cancer risk

  • Bin Hu
  • Ying Huang
  • Rong-huan Yu
  • Hong-ju Mao
  • Chao Guan
  • Jing Zhao
Research Article


Several genome-wide association studies on lung cancer (LC) have reported similar findings of a new susceptibility locus, 15q25. After that, a number of studies reported that rs8034191 and rs1051730 polymorphisms at chromosome 15q25 have been implicated in LC risk. However, studies have yielded contradictory results. To derive a more precise estimation of the relationship, a meta-analysis of 43,742 LC cases and 58,967 controls from 17 published case–control studies was performed. Overall, significantly elevated LC risk was associated with rs8034191-C (OR = 1.26, 95 % CI 1.22–1.31, P < 10−5) and rs105173-A variant (OR = 1.28, 95 % CI 1.20–1.36, P < 10−5) when all studies were pooled into the meta-analysis. In the subgroup analysis by ethnicity, significantly increased risks were found for rs8034191 and rs105173 polymorphisms among Caucasians and African American, while no significant associations were observed for the two polymorphisms in East Asians. In addition, we found that rs8034191 and rs105173 confer risk, for both adenocarcinoma and squamous cell carcinoma when stratified by histological types of LC. Furthermore, our results on stratified analysis according to smoking status showed an increased LC risk in ever-smokers, while no associations were detected among never-smokers for the two polymorphisms. In conclusion, this meta-analysis demonstrated that the two common variations (rs8034191 and rs1051730) at 15q25 are a risk factor associated with increased LC susceptibility, but these associations vary in different ethnic populations.


15q25 Polymorphism Lung cancer Meta-analysis 



This work was supported by grants from Shanghai Institute of Microsystem and Information Technology and Shanghai Clinical Center/ShanghaiXuhui Central Hospital, Chinese Academic of Sciences (no. BRC2012002), diagnosis and treatment of chronic airway diseases specialist features of Xuhui District (2010QTSZK-04).

Conflicts of interest


Supplementary material

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  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  2. 2.
    Tardon A, Lee W, Delgado M, Dosemeci M, Albanes D, Hoover R. Leisure-time physical activity and lung cancer: a meta-analysis. Cancer Causes Control. 2005;16:389–97.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol. 2006;24:2245–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nat Rev Cancer. 2007;7:778–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008;40:616–22.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008;452:633–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 2008;452:638–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Wang X, Zhang L, Chen Z, Ma Y, Zhao Y, Rewuti A, et al. Association between 5p12 genomic markers and breast cancer susceptibility: evidence from 19 case–control studies. PLoS One. 2013;8:e73611.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–29.CrossRefGoogle Scholar
  10. 10.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.PubMedCrossRefGoogle Scholar
  11. 11.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.PubMedGoogle Scholar
  12. 12.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.PubMedCrossRefGoogle Scholar
  13. 13.
    Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet. 1955;19:251–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.PubMedCrossRefGoogle Scholar
  15. 15.
    Egger M, Davey Smith G, Schneider M. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009;85:679–91.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Schwartz AG, Cote ML, Wenzlaff AS, Land S, Amos CI. Racial differences in the association between SNPs on 15q25.1, smoking behavior, and risk of non-small cell lung cancer. J Thorac Oncol. 2009;4:1195–201.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Zienolddiny S, Skaug V, Landvik NE, Ryberg D, Phillips DH, Houlston R, et al. The TERT-CLPTM1L lung cancer susceptibility variant associates with higher DNA adduct formation in the lung. Carcinogenesis. 2009;30:1368–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Broderick P, Wang Y, Vijayakrishnan J, Matakidou A, Spitz MR, Eisen T, et al. Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. Cancer Res. 2009;69:6633–41.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Wu C, Hu Z, Yu D, Huang L, Jin G, Liang J, et al. Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations. Cancer Res. 2009;69:5065–72.PubMedCrossRefGoogle Scholar
  21. 21.
    Miki D, Kubo M, Takahashi A, Yoon KA, Kim J, Lee GK, et al. Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat Genet. 2010;42:893–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Amos CI, Gorlov IP, Dong Q, Wu X, Zhang H, Lu EY, et al. Nicotinic acetylcholine receptor region on chromosome 15q25 and lung cancer risk among African Americans: a case–control study. J Natl Cancer Inst. 2010;102:1199–205.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Truong T, Hung RJ, Amos CI, Wu X, Bickeböller H, Rosenberger A, et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst. 2010;102:959–71.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Girard N, Lou E, Azzoli CG, Reddy R, Robson M, Harlan M, et al. Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Clin Cancer Res. 2010;16:755–63.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Kohno T, Kunitoh H, Mimaki S, Shiraishi K, Kuchiba A, Yamamoto S, et al. Contribution of the TP53, OGG1, CHRNA3, and HLA-DQA1 genes to the risk for lung squamous cell carcinoma. J Thorac Oncol. 2011;6:813–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Jaworowska E, Trubicka J, Lener MR, Masojć B, Złowocka-Perłowska E, McKay JD, et al. Smoking related cancers and loci at chromosomes 15q25, 5p15, 6p22.1 and 6p21.33 in the Polish population. PLoS One. 2011;6:e25057.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Ito H, McKay JD, Hosono S, Hida T, Yatabe Y, Mitsudomi T, et al. Association between a genome-wide association study-identified locus and the risk of lung cancer in Japanese population. J Thorac Oncol. 2012;7:790–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Shiraishi K, Kunitoh H, Daigo Y, Takahashi A, Goto K, Sakamoto H, et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet. 2012;44:900–3.PubMedCrossRefGoogle Scholar
  29. 29.
    VanderWeele TJ, Asomaning K, Tchetgen Tchetgen EJ, Han Y, Spitz MR, Shete S, et al. Genetic variants on 15q25.1, smoking, and lung cancer: an assessment of mediation and interaction. Am J Epidemiol. 2012;175:1013–20.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Lan Q, Hsiung CA, Matsuo K, Hong YC, Seow A, Wang Z, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet. 2012;44:1330–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Tokuhata GK, Lilienfeld AM. Familial aggregation of lung cancer in humans. J Natl Cancer Inst. 1963;30:289–312.PubMedGoogle Scholar
  32. 32.
    Matakidou A, Eisen T, Houlston RS. Systematic review of the relationship between family history and lung cancer risk. Br J Cancer. 2005;93:825–33.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Berrettini W, Yuan X, Tozzi F, Song K, Francks C, Chilcoat H, et al. Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry. 2008;13:368–73.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D, Saccone SF, et al. The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Res. 2009;69:6848–56.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Weiss RB, Baker TB, Cannon DS, von Niederhausern A, Dunn DM, Matsunami N, et al. A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet. 2008;4:e1000125.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Spitz MR, Amos CI, Dong Q, Lin J, Wu X. The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. J Natl Cancer Inst. 2008;100:1552–6.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Zhang Q, Tang X, Zhang ZF, Velikina R, Shi S, Le AD. Nicotine induces hypoxia-inducible factor-1alpha expression in human lung cancer cells via nicotinic acetylcholine receptor-mediated signaling pathways. Clin Cancer Res. 2007;13:4686–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Lam DC, Girard L, Ramirez R, Chau WS, Suen WS, Sheridan S, et al. Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res. 2007;67:4638–47.PubMedCrossRefGoogle Scholar
  39. 39.
    Minna JD. Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer. J Clin Invest. 2003;111:31–3.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Trombino S, Cesario A, Margaritora S, Granone P, Motta G, Falugi C, et al. Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway. Cancer Res. 2004;64:135–45.PubMedCrossRefGoogle Scholar
  41. 41.
    Ho YS, Chen CH, Wang YJ, Pestell RG, Albanese C, Chen RJ, et al. Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation. Toxicol Appl Pharmacol. 2005;205:133–48.PubMedCrossRefGoogle Scholar
  42. 42.
    Song P, Sekhon HS, Fu XW, Maier M, Jia Y, Duan J, et al. Activated cholinergic signaling provides a target in squamous cell lung carcinoma. Cancer Res. 2008;68:4693–700.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Bin Hu
    • 1
  • Ying Huang
    • 1
  • Rong-huan Yu
    • 1
  • Hong-ju Mao
    • 2
  • Chao Guan
    • 1
  • Jing Zhao
    • 3
  1. 1.Department of Respiratory MedicineShanghai Xuhui District Center HospitalShanghaiPeople’s Republic of China
  2. 2.State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information TechnologyChinese Academy of SciencesShanghaiPeople’s Republic of China
  3. 3.Department of Respiratory MedicineAffiliated Hospital of Nantong UniversityNantongPeople’s Republic of China

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