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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)663-673
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume195
Issue number5
DOIs
Publication statusPublished - Mar 1 2017
Externally publishedYes

Fingerprint

Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Disease-Free Survival
Smoking
Single Nucleotide Polymorphism
Non-Small Cell Lung Carcinoma
Adenocarcinoma of lung
Genome-Wide Association Study
Pharmacogenetics
Therapeutics
G-Protein-Coupled Receptors
Platinum
Genes
Lung Neoplasms
Cell Death
Biomarkers
Genome
Ligands
Drug Therapy
Mutation

Keywords

  • Genome-wide association study
  • Lung neoplasms
  • Molecular targeted therapy
  • Neversmokers
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors. / Chang, I. Shou; Jiang, Shih Sheng; Yang, James Chih Hsin; Su, Wu Chou; Chien, Li Hsin; Hsiao, Chin Fu; Lee, Jih Hsiang; Chen, Chih Yi; Chen, Chung Hsing; Chang, Gee Chen; Wang, Zhaoming; Lo, Fang Yi; Chen, Kuan Yu; Wang, Wen Chang; Chen, Yuh Min; Huang, Ming Shyan; Tsai, Ying Huang; Su, Yu Chun; Hsieh, Wan Shan; Shih, Wen Chi; Shieh, Shwn Huey; Yang, Tsung Ying; Lan, Qing; Rothman, Nathaniel; Chen, Chien Jen; Chanock, Stephen J.; Yang, Pan Chyr; Hsiung, Chao A.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 195, No. 5, 01.03.2017, p. 663-673.

Research output: Contribution to journalArticle

Chang, IS, Jiang, SS, Yang, JCH, 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 2017, 'Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors', American Journal of Respiratory and Critical Care Medicine, vol. 195, no. 5, pp. 663-673. https://doi.org/10.1164/rccm.201602-0300OC
Chang, I. Shou ; Jiang, Shih Sheng ; Yang, James Chih Hsin ; Su, Wu Chou ; Chien, Li Hsin ; Hsiao, Chin Fu ; Lee, Jih Hsiang ; Chen, Chih Yi ; Chen, Chung Hsing ; Chang, Gee Chen ; Wang, Zhaoming ; Lo, Fang Yi ; Chen, Kuan Yu ; Wang, Wen Chang ; Chen, Yuh Min ; Huang, Ming Shyan ; Tsai, Ying Huang ; Su, Yu Chun ; Hsieh, Wan Shan ; Shih, Wen Chi ; Shieh, Shwn Huey ; Yang, Tsung Ying ; Lan, Qing ; Rothman, Nathaniel ; Chen, Chien Jen ; Chanock, Stephen J. ; Yang, Pan Chyr ; Hsiung, Chao A. / Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors. In: American Journal of Respiratory and Critical Care Medicine. 2017 ; Vol. 195, No. 5. pp. 663-673.
@article{e697f43c4a484cf68bf773bbde506c6e,
title = "Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors",
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 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.",
keywords = "Genome-wide association study, Lung neoplasms, Molecular targeted therapy, Neversmokers, Single-nucleotide polymorphism",
author = "Chang, {I. Shou} and Jiang, {Shih Sheng} and Yang, {James Chih Hsin} and Su, {Wu Chou} and Chien, {Li Hsin} and Hsiao, {Chin Fu} and Lee, {Jih Hsiang} and Chen, {Chih Yi} and Chen, {Chung Hsing} and Chang, {Gee Chen} and Zhaoming Wang and Lo, {Fang Yi} and Chen, {Kuan Yu} and Wang, {Wen Chang} and Chen, {Yuh Min} and Huang, {Ming Shyan} and Tsai, {Ying Huang} and Su, {Yu Chun} and Hsieh, {Wan Shan} and Shih, {Wen Chi} and Shieh, {Shwn Huey} and Yang, {Tsung Ying} and Qing Lan and Nathaniel Rothman and Chen, {Chien Jen} and Chanock, {Stephen J.} and Yang, {Pan Chyr} and Hsiung, {Chao A.}",
year = "2017",
month = "3",
day = "1",
doi = "10.1164/rccm.201602-0300OC",
language = "English",
volume = "195",
pages = "663--673",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "5",

}

TY - JOUR

T1 - Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors

AU - Chang, I. Shou

AU - Jiang, Shih Sheng

AU - Yang, James Chih Hsin

AU - Su, Wu Chou

AU - Chien, Li Hsin

AU - Hsiao, Chin Fu

AU - Lee, Jih Hsiang

AU - Chen, Chih Yi

AU - Chen, Chung Hsing

AU - Chang, Gee Chen

AU - Wang, Zhaoming

AU - Lo, Fang Yi

AU - Chen, Kuan Yu

AU - Wang, Wen Chang

AU - Chen, Yuh Min

AU - Huang, Ming Shyan

AU - Tsai, Ying Huang

AU - Su, Yu Chun

AU - Hsieh, Wan Shan

AU - Shih, Wen Chi

AU - Shieh, Shwn Huey

AU - Yang, Tsung Ying

AU - Lan, Qing

AU - Rothman, Nathaniel

AU - Chen, Chien Jen

AU - Chanock, Stephen J.

AU - Yang, Pan Chyr

AU - Hsiung, Chao A.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

KW - Genome-wide association study

KW - Lung neoplasms

KW - Molecular targeted therapy

KW - Neversmokers

KW - Single-nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85014794974&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014794974&partnerID=8YFLogxK

U2 - 10.1164/rccm.201602-0300OC

DO - 10.1164/rccm.201602-0300OC

M3 - Article

C2 - 27669169

AN - SCOPUS:85014794974

VL - 195

SP - 663

EP - 673

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 5

ER -