A variant of the Cockayne syndrome B gene ERCC6 confers risk of lung cancer

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= × 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. Hum Mutat 29(1), 113–122, 2008. Published 2007, Wiley-Liss, Inc.