title: Functional genetic variants of c-Jun and their interaction with smoking and drinking increase the susceptibility to lung cancer in southern and eastern Chinese.
abstract: Human proto-oncogene c-Jun and c-Fos assemble the activator protein-1 complex which is a crucial transcription factor responding to environmental factors and promotes tumorgenesis. We hypothesized that genetic variants in these two genes may alter the carriers' susceptibility to lung cancer. In two independent case-control studies, we genotyped three putative functional polymorphisms (-1318T>G and -673T>C of c-Jun; -60C>T of c-Fos) in southern Chinese and then validated the association in eastern Chinese. We found that compared to -1318TT genotype, the -1318GT/GG variant genotypes had an increased lung cancer risk (OR=1.46, 95% CI=1.26-1.69), and the -673CC genotype had an increased lung cancer risk compared to -673TT/CT genotypes (OR=1.35, 95% CI=1.17-1.56) in the total 1,559 cases versus 1,679 controls. After combining these two loci, the number of the risk genotypes was associated with increased cancer risk in a dose-response manner (ptrend=2.21×10(-11)); moreover, the risk genotypes interacted with smoking or drinking status on increasing cancer risk (p values of interaction were 0.009 and 0.007, respectively). Further, we found that those with -1318GT/GG genotypes, -673CC genotypes or both genotypes in c-Jun had higher mRNA and protein expression levels in vivo, and those variants had higher transcription activities in reporter genes in vitro, especially under the stimuli with tobacco extract or alcohol mixture as luciferase assay shown. However, for -60C>T of c-Fos, no significant association was observed for lung cancer risk. Our data suggested that the genetic variants in c-Jun (-1318T>G and -673T>C) increase the carriers' susceptibility to lung cancer via interaction with smoking or drinking on increasing the c-Jun's expression.
authors.affiliation: The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Binfang
authors.initials: B
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Li
authors.forename: Mei
authors.initials: M
authors.lastname: Cheng
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Huang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Qingchu
authors.initials: Q
authors.lastname: Li
authors.forename: Weidong
authors.initials: W
authors.lastname: Ji
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jiachun
authors.initials: J
authors.lastname: Lu
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000209:etiology / Q000473:pathology; D000428:Alcohol Drinking / Q000009:adverse effects* / Q000235:genetics; D015153:Blotting, Western; D018287:Carcinoma, Large Cell / Q000453:epidemiology / Q000209:etiology / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000209:etiology / Q000473:pathology; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D005260:Female; D059647:Gene-Environment Interaction; D016762:Genes, fos; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007124:Immunoenzyme Techniques; D015994:Incidence; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D055752:Small Cell Lung Carcinoma / Q000453:epidemiology / Q000209:etiology / Q000473:pathology; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D008156:Luciferases