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TERT Polymorphism rs2736100-C Is Associated with EGFR Mutation-Positive Non-Small Cell Lung Cancer.

ABSTRACT: 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.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.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.Our study suggests that telomerase and telomere function may be essential for carcinogenesis of EGFRmut(+) NSCLC. Further investigation for the underlying mechanism is warranted.

SUBMITTER: Wei R

PROVIDER: S-EPMC4644673 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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TERT Polymorphism rs2736100-C Is Associated with EGFR Mutation-Positive Non-Small Cell Lung Cancer.

Wei Rongrong R Cao Lan L Pu Hengying H Wang Hongwei H Zheng Yonglan Y Niu Xiaomin X Weng Xiaoling X Zhang Hong H Favus Murray M Zhang Lanjun L Jia Weihua W Zeng Yixin Y Amos Christopher I CI Lu Shun S Wang Hui-Yun HY Liu Yun Y Liu Wanqing W

Clinical cancer research : an official journal of the American Association for Cancer Research 20150706 22

<h4>Purpose</h4>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.<h4>Experimental de ...[more]

PMID: 26149460

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Project description:BackgroundFew studies have compared the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), afatinib, with that of reversible EGFR-TKIs. Therefore, this study assessed the effectiveness of afatinib, erlotinib, and gefitinib in terms of OS (overall survival) and progression-free survival (PFS) in EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) patients.MethodsPatients with EGFR mutation-positive advanced NSCLC who sought treatment from December 2013 to June 2018, at a tertiary referral center were retrospectively analyzed. These patients were treated with afatinib or a reversible EGFR-TKI (erlotinib or gefitinib) until disease progression, intolerable adverse events, or death. The Kaplan-Meier and log-rank tests were then used to compare the OS and PFS of the patients. We further analyzed the survival differences among the subgroup of patients without brain metastases.ResultsOf the 363 patients enrolled, 134 and 229 received first-line afatinib and first-line reversible EGFR-TKI, respectively. Those given afatinib had better OS (39.3 vs. 26.0 months; HR 0.65, P = 0.033) and PFS (14.1 vs.11.2 months; HR 0.58, P < 0.001). Of the 246 patients without brain metastases, 93 and 153 received first-line afatinib and a first-line reversible EGFR-TKI, respectively. Those given afatinib had a better OS (52.6 vs. 24.9 months; HR 0.62, P = 0.0030) and PFS (17.7 vs. 11.1 months; HR 0.51, P < 0.001). The survival benefit was more significant in the subgroup of patients with L858R substitutions.ConclusionsThe results indicated that afatnib resulted in significantly better OS and PFS than gefitnib and erlotinib for EGFR mutation-positive advanced NSCLC patients without brain metastases.Key pointsSignificant findings of the study Afatnib resulted in significantly better overall survival and progression-free survival than gefitnib and erlotinib for EGFR mutation-positive advanced non-small cell lung cancer patients without brain metastases. What this study adds This study helps fill the gap in our limited understanding of the differences in the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), afatinib, with that of reversible EGFR-TKIs.

Dataset Information

TERT Polymorphism rs2736100-C Is Associated with EGFR Mutation-Positive Non-Small Cell Lung Cancer.

Publications

TERT Polymorphism rs2736100-C Is Associated with EGFR Mutation-Positive Non-Small Cell Lung Cancer.

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