國家衛生研究院 NHRI:Item 3990099045/10019
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    题名: Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line TKIs
    作者: Chang, IS;Jiang, SS;Yang, JC;Su, WC;Chien, LH;Hsiao, CF;Lee, JH;Chen, CY;Chen, CH;Chang, GC;Wang, Z;Lo, FY;Chen, KY;Wang, WC;Chen, YM;Huang, MS;Tsai, YH;Su, YC;Hsieh, WS;Shih, WC;Shieh, SH;Yang, TY;Lan, Q;Rothman, N;Chen, CJ;Chanock, SJ;Yang, PC;Hsiung, CA
    贡献者: National Institute of Cancer Research;Division of Clinical Trial Statistics;Division of Biostatistics and Bioinformatics
    摘要: RATIONALE: Patients of NSCLC with mutated EGFR are relatively sensitive to EGFR-TKI treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI, compared with platinum-based chemotherapy. However, many advanced NSCLC patients with mutated EGFR do not response to first-line EGFR-TKI treatment and still have shorter PFS. OBJECTIVES: The aim of this study was to identify genetic variants associated PFS among lung adenocarcinoma (ADC) patients 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 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<10-8) and with an estimated hazard ratio greater than 4. This association was also replicated in a larger but similar cohort as well as in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs are associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene NMU, which encodes a GPCR ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers in the treatment of late-stage lung cancer patients, we found that these SNPs were not associated with EGFR mutation status, or with BIM polymorphism. 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.
    日期: 2017-03
    關聯: American Journal of Respiratory and Critical Care Medicine. 2017 Mar;195(5):663-673.
    Link to: http://dx.doi.org/10.1164/rccm.201602-0300OC
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1073-449X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000395357400016
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85014794974
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