A variant of the Cockayne syndrome B geneERCC6 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= × 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.