title: TERT Polymorphism rs2736100-C Is Associated with EGFR Mutation-Positive Non-Small Cell Lung Cancer.
abstract: OBJECTIVE
  EGF receptor (EGFR) mutation-positive (EGFRmut(+)) non-small cell lung cancer (NSCLC) may be a unique orphan disease. Previous studies suggested that the telomerase reverse transcriptase (TERT) gene polymorphism is associated with demographic and clinical features strongly associated with EGFR mutations, for example, adenocarcinoma histology, never-smoking history, and female gender. We aim to test the association between TERT polymorphism and EGFRmut(+) NSCLC.
  
  
  METHODS
  We conducted a genetic association study in Chinese patients with NSCLC (n = 714) and healthy controls (n = 2,520), between the rs2736100 polymorphism and EGFRmut(+) NSCLC. We further tested the association between the EGFR mutation status and mean leukocyte telomere length (LTL). The potential function of rs2736100 in lung epithelial cells was also explored.
  
  
  RESULTS
  The rs2736100-C allele was significantly associated with EGFRmut(+) NSCLC [OR, 1.52; 95% confidence interval (CI), 1.28-1.80; P = 1.6 × 10(-6)] but not EGFRmut(-) NSCLC (OR = 1.07, 95% CI, 0.92-1.24, P = 0.4). While patients with NSCLC as a whole have significantly longer LTL than healthy controls (P ≤ 10(-13)), the EGFRmut(+) patients have even longer LTL than EGFRmut(-) patients (P = 0.008). Meanwhile, rs2736100 was significantly associated with TERT mRNA expression in both normal and tumor lung tissues. All results remained significant after controlling for age, gender, smoking status, and histology (P < 0.05 for all tests). Moreover, the rs2736100 DNA sequence has an allele-specific affinity to nuclear proteins extracted from lung epithelial cells, which led to an altered enhancer activity of the sequence in vitro.
  
  
  CONCLUSIONS
  Our study suggests that telomerase and telomere function may be essential for carcinogenesis of EGFRmut(+) NSCLC. Further investigation for the underlying mechanism is warranted.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wei
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China.
authors.forename: Hengying
authors.initials: H
authors.lastname: Pu
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, P. R. China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Niu
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Weng
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Favus
authors.affiliation: Department of Thoracic Surgery, Sun Yat-Sen University Cancer Centre, Guangzhou, P. R. China.
authors.forename: Lanjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, P. R. China.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors; C509186:TERT protein, human; D019098:Telomerase