title: A variant of the Cockayne syndrome B gene ERCC6 confers risk of lung cancer.
abstract: Cockayne syndrome B protein (ERCC6) plays an essential role in DNA repair. However, the Cockayne syndrome caused by the ERCC6 defect has not been linked to cancer predisposition; likely due to the fact that cells with severe disruption of the ERCC6 function are sensitive to lesion-induced apoptosis, thus reducing the chance of tumorigenesis. The biological function and cancer susceptibility of a common variant rs3793784:C>G (c.-6530C>G) in the ERCC6 was examined. We show that the c.-6530C allele has lower binding affinity of Sp1 by EMSA and displays a lower transcriptional activity in vitro and in vivo. We then examined the contribution of this polymorphism to the risk of lung cancer in a case-control study with 1,000 cases and 1,000 controls. The case-control analysis revealed a 1.76-fold (P= x 10(-9)) excess risk of developing lung cancer for the c.-6530CC carriers compared with noncarriers. The c.-6530CC interacts with smoking to intensify lung cancer risk, with the odds ratio (OR)=9 for developing lung cancer among heavy smokers. Our data constituted strong evidence that ERCC6 rs3793784:C>G alters its transcriptional activity and may confer personalized susceptibility to lung cancer.
authors.affiliation: Division of Personalized Nutrition and Medicine, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA.
authors.forename: Zhongning
authors.initials: Z
authors.lastname: Lin
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Tuo
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guo
authors.forename: Bridgett
authors.initials: B
authors.lastname: Green
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ling
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
authors.forename: Baitang
authors.initials: B
authors.lastname: Ning
mesh_terms: D000483:Alleles; D044466:Asian People; D001483:Base Sequence; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008969:Molecular Sequence Data; D000075223:Poly-ADP-Ribose Binding Proteins; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes