Abstract
We searched for potential regulatory single nucleotide polymorphisms (SNPs) in excision repair cross-complementing group 1 (ERCC1) using RegulomeDB, a database integrating information from the Encyclopedia of DNA Elements (ENCODE) project, and investigated their association with survival after surgery in non-small cell lung cancer (NSCLC). Among 364 SNPs found within ERCC1 region using RegulomeDB, four top priority SNPs (rs2298881C>A, rs1049739A>G, rs10415949A>G and rs6509214G>T) were selected for this study. The four SNPs were investigated in 316 patients. A replication study was performed (n = 579). Of the four SNPs analyzed in the discovery set, rs2298881C>A and rs6509214G>T were significantly associated with survival outcomes. The association was consistently observed only for rs2298881C>A in the validation cohort. In combined analysis, rs2298881C>A was significantly associated with worse overall survival and disease-free survival (P = 0.0002 and 0.02, respectively). A decreased reporter gene expression for rs2298881 A allele was observed compared with C allele by luciferase assay (P = 0.02). ERCC1 rs2298881C>A, an intronic SNP, is the first genetic polymorphism with functional evidence of regulating its expression, and the SNP is associated with prognosis of NSCLC. Our result supports the role of RegulomeDB as a comprehensive source of prioritized candidate SNPs for genetic association studies.
Highlights
Excision repair cross-complementing group 1 (ERCC1) is involved in nucleotide excision repair pathway that eliminates bulky DNA adducts caused by carcinogens in tobacco smoke and platinum-based chemotherapeutic agents [1, 2]
We investigated the association between potential regulatory single nucleotide polymorphisms (SNPs) in ERCC1 gene region selected from RegulomeDB and survival of patients with surgically resected early stage non-small cell lung cancer (NSCLC) in a relatively large two-stage study including 895 patients
Our study showed significant association between ERCC1 rs2298881C>A and the prognosis of patients with early stage NSCLC, which was reproducible in an independent set of patients
Summary
Excision repair cross-complementing group 1 (ERCC1) is involved in nucleotide excision repair pathway that eliminates bulky DNA adducts caused by carcinogens in tobacco smoke and platinum-based chemotherapeutic agents [1, 2]. ERCC1 has been linked to protection against development and progression of cancer, and resistance to platinum-based anticancer drugs at the same time: the double-edged sword. The expression of ERCC1 by quantitative real-time polymerase chain reaction or immunohistochemistry has been correlated with the clinical outcomes of non-small cell lung cancer (NSCLC) [3,4,5]. Genetic polymorphism of ERCC1 has been investigated for the association with the risk and clinical outcome of many types of cancer including NSCLC [6,7,8,9,10,11,12,13,14]. The most widely studied single nucleotide polymorphisms (SNPs) include rs11615T>C (N118N) which is the only SNP tested in the exon region of ERCC1, and rs3212986C>A in 3′- UTR of ERCC1 (Q504K for CD3EAP, antisense to ERCC1). The association of these SNPs with NSCLC has not been consistent across studies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
