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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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).
McKay, J.D. et al. Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404–1406 (2008).
Wang, Y. et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat. Genet. 40, 1407–1409 (2008).
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).
Miki, D. et al. Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat. Genet. 42, 893–896 (2010).
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).
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).
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).
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).
Thorgeirsson, T.E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).
Zeller, T. et al. Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).
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).
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).
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).
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).
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).
Edelman, A.M., Blumenthal, D.K. & Krebs, E.G. Protein serine/threonine kinases. Annu. Rev. Biochem. 56, 567–613 (1987).
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).
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).
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).
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).
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).
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).
Chen, G. et al. CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma. Clin. Cancer Res. 17, 817–826 (2011).
Matsunawa, M. et al. The aryl hydrocarbon receptor activator benzo[a]pyrene enhances vitamin D3 catabolism in macrophages. Toxicol. Sci. 109, 50–58 (2009).
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).
Huang, M. et al. Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res. 55, 3847–3853 (1995).
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).
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).
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).
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).
Moffatt, M.F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).
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).
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).
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).
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).
Habbig, S. et al. NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J. Cell Biol. 193, 633–642 (2011).
Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).
Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).
Veyrieras, J.B. et al. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 4, e1000214 (2008).
Pickrell, J.K. et al. Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464, 768–772 (2010).
Montgomery, S.B. et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010).
Dimas, A.S. et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009).
Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).
Myers, A.J. et al. A survey of genetic human cortical gene expression. Nat. Genet. 39, 1494–1499 (2007).
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.
The authors declare no competing financial interests.
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