Study Of The Biological Function And Underlying Mechanism Of Genetic Variations In The Enhancer Within 13q12.12 Lung Cancer Risk Region

Lung cancer is a common complex disease.It is resulted from environmental and genetic factors.Single Nucleotide Polymorphism(SNP)is one of the most common genetic variations,and its role in the development of cancer is becoming more and more important which has become a hot spot in the field of cancer research.99%of the genomeare non-coding sequence in the human and scattered in a lot of regulatory elements.The DNA element Encyclopedia(ENCODE)program has revealed that most of the regulatory elements in the non-codingregion are enhancers.Enhancer is a special DNA sequence in the genome,usually located in the open chromatin region,with characteristic histone modifications(high abundance of H3K4me1 and H3K27ac,low abundance H3K4me3)and rich transcription factor binding sites.Alarge number ofgenome wide association analyze(GWAS)results showed that most of the disease-associated risk SNPs are located in the enhancers,suggesting that the dysfunction of the enhancers caused by SNPs has an inherent relationship with the susceptibility to disease.In this study,we characterized a novel p53-responsive enhancer,13q-Enh2.It harbors three common genetic variations in high linkage disequilibrium with the risk SNP rs753955 within non-coding region of the 13q12.12 risk locus that is highly associated with lung cancer risk in the Chinese population.Our data indicate this enhancer protects Beas-2B bronchial epithelial cells from a potent pulmonary carcinogen NNK-induced DNA damage and malignant transformation by activating the TNFRSF19 target gene 180kb upstream,while the three linked genetic variations attenuate enhancer activity by interfering with the p53 enhancer reaction.Our eQTL analysis of 117 Chinese NSCLC samples and GTEx data supported suppressive effects of mutant alleles on TNFRSF19 expression and a close relationship to high tumor staging and short survival time.The genetic variations of a newly identified p53-responsive enhancer and resultant TNFRSF19 deregulation may serve as a mechanism of lung cancer pathogenesis.