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Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population

Abstract

To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS)1 of lung cancer in the Chinese population in an extended validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10−8) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10−10), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10−9) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10−8). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10−8) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10−6). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10−10, P = 5.07 × 10−3, P = 6.77 × 10−3 and P = 4.49 × 10−2 for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer.

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Figure 1: Regional plots of the five identified marker SNPs (rs1663689 at 10p14, rs2895680 at 5q32, rs4809957 at 20q13.2, rs247008 at 5q31.1 and rs9439519 at 1p36.32).

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References

  1. Hu, Z. et al. A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat. Genet. 43, 792–796 (2011).

    Article  CAS  Google Scholar 

  2. McKay, J.D. et al. Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404–1406 (2008).

    Article  CAS  Google Scholar 

  3. Wang, Y. et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat. Genet. 40, 1407–1409 (2008).

    Article  CAS  Google Scholar 

  4. Hung, R.J. et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452, 633–637 (2008).

    Article  CAS  Google Scholar 

  5. Miki, D. et al. Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat. Genet. 42, 893–896 (2010).

    Article  CAS  Google Scholar 

  6. Amos, C.I. et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat. Genet. 40, 616–622 (2008).

    Article  CAS  Google Scholar 

  7. Li, Y. et al. Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol. 11, 321–330 (2010).

    Article  CAS  Google Scholar 

  8. Ahn, M.J. et al. The 18p11.22 locus is associated with never smoker non-small cell lung cancer susceptibility in Korean populations. Hum. Genet. 131, 365–372 (2012).

    Article  Google Scholar 

  9. Yoon, K.A. et al. A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. Hum. Mol. Genet. 19, 4948–4954 (2010).

    Article  CAS  Google Scholar 

  10. Thorgeirsson, T.E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).

    Article  CAS  Google Scholar 

  11. Zeller, T. et al. Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).

    Article  Google Scholar 

  12. Maurice, D., Hooper, J., Lang, G. & Weston, K. c-Myb regulates lineage choice in developing thymocytes via its target gene Gata3. EMBO J. 26, 3629–3640 (2007).

    Article  CAS  Google Scholar 

  13. Enciso-Mora, V. et al. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat. Genet. 42, 1126–1130 (2010).

    Article  CAS  Google Scholar 

  14. Yang, Y. et al. The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200–dependent pathway in mice. J. Clin. Invest. 121, 1373–1385 (2011).

    Article  CAS  Google Scholar 

  15. Tkocz, D. et al. BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers. Oncogene published online, doi:10.1038/onc.2011.531 (28 November 2011).

    Article  CAS  Google Scholar 

  16. Asselin-Labat, M.L. et al. Gata-3 negatively regulates the tumor-initiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14. Mol. Cell. Biol. 31, 4609–4622 (2011).

    Article  CAS  Google Scholar 

  17. Edelman, A.M., Blumenthal, D.K. & Krebs, E.G. Protein serine/threonine kinases. Annu. Rev. Biochem. 56, 567–613 (1987).

    Article  CAS  Google Scholar 

  18. Tan, J. et al. B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell 18, 459–471 (2010).

    Article  CAS  Google Scholar 

  19. Okita, K. et al. A set of genes associated with the interferon-γ response of lung cancer patients undergoing α-galactosylceramide-pulsed dendritic cell therapy. Cancer Sci. 101, 2333–2340 (2010).

    Article  CAS  Google Scholar 

  20. Hsiung, C.A. et al. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet. 6, e1001051 (2010).

    Article  Google Scholar 

  21. Peehl, D.M. et al. Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res. 54, 805–810 (1994).

    CAS  PubMed  Google Scholar 

  22. Kim, B. et al. Clinical validity of the lung cancer biomarkers identified by bioinformatics analysis of public expression data. Cancer Res. 67, 7431–7438 (2007).

    Article  CAS  Google Scholar 

  23. Anderson, M.G., Nakane, M., Ruan, X., Kroeger, P.E. & Wu-Wong, J.R. Expression of VDR and CYP24A1 mRNA in human tumors. Cancer Chemother. Pharmacol. 57, 234–240 (2006).

    Article  CAS  Google Scholar 

  24. Chen, G. et al. CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma. Clin. Cancer Res. 17, 817–826 (2011).

    Article  CAS  Google Scholar 

  25. Matsunawa, M. et al. The aryl hydrocarbon receptor activator benzo[a]pyrene enhances vitamin D3 catabolism in macrophages. Toxicol. Sci. 109, 50–58 (2009).

    Article  CAS  Google Scholar 

  26. Yamamura, M., Modlin, R.L., Ohmen, J.D. & Moy, R.L. Local expression of antiinflammatory cytokines in cancer. J. Clin. Invest. 91, 1005–1010 (1993).

    Article  CAS  Google Scholar 

  27. Huang, M. et al. Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res. 55, 3847–3853 (1995).

    CAS  PubMed  Google Scholar 

  28. Sorrentino, R. et al. Plasmacytoid dendritic cells prevent cigarette smoke and Chlamydophila pneumoniae–induced Th2 inflammatory responses. Am. J. Respir. Cell Mol. Biol. 43, 422–431 (2010).

    Article  CAS  Google Scholar 

  29. Vassallo, R., Tamada, K., Lau, J.S., Kroening, P.R. & Chen, L. Cigarette smoke extract suppresses human dendritic cell function leading to preferential induction of Th-2 priming. J. Immunol. 175, 2684–2691 (2005).

    Article  CAS  Google Scholar 

  30. Teodoro, J.G., Parker, A.E., Zhu, X. & Green, M.R. p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science 313, 968–971 (2006).

    Article  CAS  Google Scholar 

  31. Dougan, M. et al. A dual role for the immune response in a mouse model of inflammation-associated lung cancer. J. Clin. Invest. 121, 2436–2446 (2011).

    Article  CAS  Google Scholar 

  32. Moffatt, M.F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

    Article  CAS  Google Scholar 

  33. Wen, G., Ringseis, R. & Eder, K. Mouse OCTN2 is directly regulated by peroxisome proliferator–activated receptor α (PPARα) via a PPRE located in the first intron. Biochem. Pharmacol. 79, 768–776 (2010).

    Article  CAS  Google Scholar 

  34. Li, M.Y. et al. Roles of peroxisome proliferator–activated receptor-α and -γ in the development of non-small cell lung cancer. Am. J. Respir. Cell Mol. Biol. 43, 674–683 (2010).

    Article  CAS  Google Scholar 

  35. Chen, J. et al. ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure. PLoS ONE 6, e28790 (2011).

    Article  CAS  Google Scholar 

  36. McDonald, J.M. et al. The SHREW1 gene, frequently deleted in oligodendrogliomas, functions to inhibit cell adhesion and migration. Cancer Biol. Ther. 5, 300–304 (2006).

    Article  CAS  Google Scholar 

  37. Habbig, S. et al. NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J. Cell Biol. 193, 633–642 (2011).

    Article  CAS  Google Scholar 

  38. Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

    Article  CAS  Google Scholar 

  39. Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

    Article  CAS  Google Scholar 

  40. Veyrieras, J.B. et al. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 4, e1000214 (2008).

    Article  Google Scholar 

  41. Pickrell, J.K. et al. Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464, 768–772 (2010).

    Article  CAS  Google Scholar 

  42. Montgomery, S.B. et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010).

    Article  CAS  Google Scholar 

  43. Dimas, A.S. et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009).

    Article  CAS  Google Scholar 

  44. Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

    Article  Google Scholar 

  45. Myers, A.J. et al. A survey of genetic human cortical gene expression. Nat. Genet. 39, 1494–1499 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is funded by the China National High-Tech Research and Development Program Grant (2009AA022705) and partly funded by the National Key Basic Research Program Grant (2011CB503805) and the National Natural Science Foundation of China (30730080, 30972541 and 30901233), Jiangsu Natural Science Foundation (BK2011028), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (11KJA330001), the US National Institutes of Health Grant (U19 CA148127) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors thank all the study subjects, research staff and students who participated in this work.

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Authors

Contributions

H.S. directed the study, obtained financial support and was responsible for study design, interpretation of results and manuscript writing. J. Dong and Z.H. performed overall project management, along with C. Wu, and drafted the initial manuscript. J. Dong, Z.H., Z.L., J. Dai and R.Z. performed statistical analyses. D. Lin, T.W., Y. Shi, D. Lu, L.J., B.Z., J.L. and K.C. directed each participating study and jointly organized this study. M.C., C. Wang, Y.J., S.C., Z.Q., J.G. and C.S. were responsible for sample processing and managed the genotyping data. H.M., G.J., Z.P., Y.C., Y. Shu and L.X. were responsible for subject recruitment and sample preparation of the Nanjing samples. C. Wu, D.Y., X.L. and W.T. were responsible for subject recruitment and sample preparation of the Beijing samples. H.G., Q.D., L.L. and P.X. were responsible for subject recruitment and sample preparation of the Wuhan samples. X.Z., J.W., G.Z., H.C., B.H. and C.B. were responsible for subject recruitment and sample preparation of the Shanghai samples. Z.Y., W.W., P.G., Y.Z., H. Zhang and Y.Y. were responsible for subject recruitment and sample preparation of the Shenyang samples. L.Y. was responsible for subject recruitment and sample preparation of the Guangzhou samples. H. Zheng was responsible for subject recruitment and sample preparation of the Tianjin samples. C.I.A. was responsible for the scientific editing. F.C. oversaw the statistical analyses process. All authors approved the final manuscript.

Corresponding author

Correspondence to Hongbing Shen.

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The authors declare no competing financial interests.

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Dong, J., Hu, Z., Wu, C. et al. Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population. Nat Genet 44, 895–899 (2012). https://doi.org/10.1038/ng.2351

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