I-Shou Chang1, Shih Sheng Jiang1, James Chih-Hsin Yang2,3, Wu-Chou Su4, Li-Hsin Chien5, Chin-Fu Hsiao5,6, Jih-Hsiang Lee2, Chih-Yi Chen7,8, Chung-Hsing Chen1, Gee-Chen Chang9,10, Zhaoming Wang11, Fang-Yi Lo5, Kuan-Yu Chen12, Wen-Chang Wang5,13, Yuh-Min Chen14,15, Ming-Shyan Huang16, Ying-Huang Tsai17, Yu-Chun Su5, Wan-Shan Hsieh5, Wen-Chi Shih5, Shwn-Huey Shieh18,19, Tsung-Ying Yang10, Qing Lan20, Nathaniel Rothman20, Chien-Jen Chen21, Stephen J Chanock20, Pan-Chyr Yang22, Chao A Hsiung5. 1. 1 National Institute of Cancer Research. 2. 2 Department of Oncology and. 3. 3 Graduate Institute of Oncology and Cancer Research Center, College of Medicine and. 4. 4 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 5. 5 Institute of Population Health Sciences, and. 6. 6 Taiwan Lung Cancer Tissue/Specimen Information Resource Center, National Health Research Institutes, Zhunan, Taiwan. 7. 7 Institute of Medicine and. 8. 8 Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan. 9. 9 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 10. 10 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. 11. 11 Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, and. 12. 12 Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan. 13. 13 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology and. 14. 15 College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. 15. 14 Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 16. 16 Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 17. 17 Division of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan. 18. 18 Department of Health Services Administration and. 19. 19 Department of Nursing, China Medical University, Taichung, Taiwan; and. 20. 20 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 21. 21 Genomic Research Center, Academia Sinica, Taipei, Taiwan. 22. 22 Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
Abstract
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 patients with advanced NSCLC who 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 < 10-8) and with 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 of EGFR, which encodes the TKI 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.
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 patients with advanced NSCLC who 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 < 10-8) and with 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 of EGFR, which encodes the TKI 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.
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