Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors

I. Shou Chang, Shih Sheng Jiang, James Chih Hsin Yang, Wu Chou Su, Li Hsin Chien, Chin Fu Hsiao, Jih Hsiang Lee, Chih Yi Chen, Chung Hsing Chen, Gee Chen Chang, Zhaoming Wang, Fang Yi Lo, Kuan Yu Chen, Wen Chang Wang, Yuh Min Chen, Ming Shyan Huang, Ying Huang Tsai, Yu Chun Su, Wan Shan Hsieh, Wen Chi ShihShwn Huey Shieh, Tsung Ying Yang, Qing Lan, Nathaniel Rothman, Chien Jen Chen, Stephen J. Chanock, Pan Chyr Yang, Chao A. Hsiung

研究成果: 雜誌貢獻文章同行評審

10 引文 斯高帕斯(Scopus)

摘要

Rationale: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patientswith advanced NSCLCwho have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. Objectives: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. Methods: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). Measurements and Main Results: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P,1028) andwith an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression ofEGFR,whichencodes theTKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. Conclusions: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.
原文英語
頁(從 - 到)663-673
頁數11
期刊American Journal of Respiratory and Critical Care Medicine
195
發行號5
DOIs
出版狀態已發佈 - 三月 1 2017
對外發佈

ASJC Scopus subject areas

  • 肺和呼吸系統醫學
  • 重症監護和重症監護醫學

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