| Lung cancer is one of the most common malignancies worldwide. In China, themorbidity and mortality of lung cancer have been increasing rapidly in last twodecades, which is believed to be mainly due to continuous increases in tobaccoconsumption and environmental pollution. Lung cancer is one of main causescontributing to disease related deaths and a serious one to be resolved in public health.Epidemiological studies indicate that over80%of lung cancer cases aretobacco-related, but only a small fraction of smokers （usually <20%） develop thisdisease, suggesting that there is an inter-individual variation in genetic susceptibilityto lung cancer under the similar exposure.Genome-wide Association Study （GWAS）, emerging with the completion ofHuman Genome Project as well as promotion of HapMap and advances in genotypingtechnology, is one of the powerful tools for genetic susceptibility study of complexdiseases. To date, GWAS have achieved considerable success in deciphering thegenetic basis of lung cancer in both European ancestry and Asian populations,identifying several lung cancer susceptibility loci, such as chromosomes5p15,6p21and15q25. We recently reported a multistage GWAS of lung cancer in the Chinesepopulation, with two newly identified （13q12.12and22q12.2） and two replicated loci（3q28and5p15.33） for lung cancer susceptibility.Although previous GWAS have provided valuable clues of the etiology of lungcancer, additional genetic factors, especially those having relatively moderate Pvalues at GWA scan remain to be discovered. In addition, the etiology of differenthistological subtypes lung cancer are heterogeneous. For example, although tobaccosmoking increases the risk of all major histological subtypes of lung cancer, it appearsto be stronger for squamous cell carcinoma （SqCC） than adenocarcinoma （AC）. Currently, SqCC and AC are regarded as an independent disease because of theirdifferent pathogenesis and biological characteristics, and respond differently totherapy. Therefore, investigating specifically histological subtype of lung cancer maydo more for lung cancer prevention and treatment. Recently, a GWAS of lung ACidentified a susceptibility locus at TP63on3q28in Asian （Japanese and Korean）populations. However, no GWAS focused on lung SqCC was reported in Asian todate.Therefore, we conducted an evaluation of promising associations for lung cancerin an extended two-stage replication, and further performed a GWAS of SqCC toassess SqCC specified susceptibily loci. Finally, we evaluated the role ofgene-environment （i.e. cigarette smoking） interactions in lung cancer and SqCC risk.The results of our study will be helpful for determining the genetic factors of lungcancer and SqCC in Chinese population and elucidating the susceptibility mechanismin lung cancer and SqCC.Part I: Association Analyses Identifies Multiple New LungCancer Susceptibility Loci and Their Interactions withSmoking in Chinese PopulationGenome-wide association studies （GWAS） have identified several susceptibilityloci for lung cancer in both European and Asian populations, but completed studiesonly account for a small fraction of the genetic risk of the disease. Four loci,including two newly identified （13q12.12and22q12.2） and two replicated loci （3q28and5p15.33）, for lung cancer susceptibility were reported through a multistageGWAS of lung cancer in Chinese, involving2,331cases and3,077controls for GWAscan, followed by a two-stage validation on6,313cases and6,409controls. To findadditional loci, we tested promising associations (1.0×10-4 P1.0×10-6) from theChinese lung cancer GWAS in an extended validation sample size of7,436cases and7,483controls. We found strong evidence for three additional lung cancer susceptibility loci atgenome-wide significant level (P <5.0×10-8) located at10p14(rs1663689close toGATA3, P=2.84×10-10),5q32(rs2895680in PPP2R2B-STK32A-DPYSL3, P=6.60×10-9) and20q13.2(rs4809957in CYP24A1, P=1.20×10-8). Consistentassociations were also found for rs247008at5q31.1(IL3-CSF2-P4HA2, P=7.68×10-8) and rs9439519at1p36.32（AJAP1-NPHP4, P=3.65×10-6）. Interestingly,four of these loci showed evidence for interactions with smoking dose (P=1.72×10-10,5.07×10-3,6.77×10-3and4.49×10-2for rs2895680, rs4809957, rs247008andrs9439519, respectively).These results advanced our understanding of the susceptibility of lung cancerand highlighted potential pathways that integrate genetic variants and smoking inlung cancer development.Part II: A Genome-Wide Association Study Identifies NovelLung Squmous Cell Carcinoma Susceptibility Loci at12q23.1in Han ChineseThe reported lung cancer GWAS almost investigated various histological lungcancer patients, while the etiology of different histological subtypes lung cancer existheterogeneity. For example, although tobacco smoking increases the risk of all majorhistological subtypes of lung cancer, it appears to be stronger for SqCC than AC.Currently, SqCC and AC are regarded as an independent disease because of theirdifferent pathogenesis and biological characteristics, and respond differently totherapy. Recently, a GWAS of lung AC identified a susceptibility locus at TP63on3q28in Asian population （Japanese and Korean）. However, no GWAS focused onlung SqCC was reported in Asian to date.We performed a multi-stage case-control study to identify lung SqCC specificsusceptibility loci based on our previous GWAS of lung cancer in Chinese. ThoseSNPs with P1.0×10-4in the GWA scan of844SqCC cases and3,160controls were chosen for further validation that consist of822SqCC cases and2,243controls in thefirst stage validation and1,401SqCC cases and4,166controls in the second stagevalidation.We found strong evidence for SqCC susceptibility loci located at12q23.1(rs12296850in SLC17A8-NR1H4, Odds Ratio （OR）=0.78, P=1.19×10-10). Comparedwith those carrying AA genotype, subjects carrying AG and GG genotypes have26%and32%decreased SqCC risk, respectively（95%Confidence Interval （CI）=0.67-0.81and0.56-0.83, respectively）. We further detected rs12296850in AC patients to test itsspecificity for SqCC. We didn’t observe any significant associations betweenrs12296850and AC risk （P=0.173）.Our results indicated that genetic variation in the SLC17A8-NR1H4locus ofchromosome12q23.1may be SqCC specific susceptibility loci. |
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