Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.
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.



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.



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).



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.



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.
1 National Institute of Cancer Research.
I-Shou
IS
Chang
1 National Institute of Cancer Research.
Shih Sheng
SS
Jiang
2 Department of Oncology and.|3 Graduate Institute of Oncology and Cancer Research Center, College of Medicine and.
James Chih-Hsin
JC
Yang
4 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wu-Chou
WC
Su
5 Institute of Population Health Sciences, and.
Li-Hsin
LH
Chien
5 Institute of Population Health Sciences, and.|6 Taiwan Lung Cancer Tissue/Specimen Information Resource Center, National Health Research Institutes, Zhunan, Taiwan.
Chin-Fu
CF
Hsiao
2 Department of Oncology and.
Jih-Hsiang
JH
Lee
7 Institute of Medicine and.|8 Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
Chih-Yi
CY
Chen
1 National Institute of Cancer Research.
Chung-Hsing
CH
Chen
9 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|10 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Gee-Chen
GC
Chang
11 Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, and.
Zhaoming
Z
Wang
5 Institute of Population Health Sciences, and.
Fang-Yi
FY
Lo
12 Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
Kuan-Yu
KY
Chen
5 Institute of Population Health Sciences, and.|13 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology and.
Wen-Chang
WC
Wang
15 College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|14 Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Yuh-Min
YM
Chen
16 Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Ming-Shyan
MS
Huang
17 Division of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.
Ying-Huang
YH
Tsai
5 Institute of Population Health Sciences, and.
Yu-Chun
YC
Su
5 Institute of Population Health Sciences, and.
Wan-Shan
WS
Hsieh
5 Institute of Population Health Sciences, and.
Wen-Chi
WC
Shih
18 Department of Health Services Administration and.|19 Department of Nursing, China Medical University, Taichung, Taiwan; and.
Shwn-Huey
SH
Shieh
10 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Tsung-Ying
TY
Yang
20 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
Qing
Q
Lan
20 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
Nathaniel
N
Rothman
21 Genomic Research Center, Academia Sinica, Taipei, Taiwan.
Chien-Jen
CJ
Chen
20 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
Stephen J
SJ
Chanock
22 Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
Pan-Chyr
PC
Yang
5 Institute of Population Health Sciences, and.
Chao A
CA
Hsiung
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D055815:Young Adult
D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
genome-wide association study; lung neoplasms; molecular targeted therapy; never-smokers; single-nucleotide polymorphism
PLoS Biol. 2011 Apr;9(4):e1001046
21526222
J Clin Oncol. 2013 Sep 20;31(27):3327-34
23816960
Nat Med. 2012 Mar 18;18(4):521-8
22426421
N Engl J Med. 2010 Jun 24;362(25):2380-8
20573926
J Thorac Oncol. 2014 Sep;9(9):1385-92
25057939
J Clin Oncol. 2006 Apr 10;24(11):1700-4
16505411
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
Clin Cancer Res. 2010 Sep 1;16(17):4401-10
20810387
Am J Respir Crit Care Med. 2015 Aug 1;192(3):283-94
26230235
Lancet Oncol. 2012 Mar;13(3):239-46
22285168
Cell Signal. 2007 Dec;19(12):2417-27
17658730
Methods Mol Biol. 2007;373:157-76
17185765
Nat Genet. 2012 Dec;44(12):1330-5
23143601
Ann Oncol. 2005;16 Suppl 2:ii229-32
15958463
Lancet Oncol. 2014 Feb;15(2):213-22
24439929
Science. 2004 Jun 4;304(5676):1497-500
15118125
Am J Respir Crit Care Med. 2013 Oct 15;188(8):907-12
23721055
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
15329413
N Engl J Med. 2004 May 20;350(21):2129-39
15118073
Nat Genet. 2013 Jun;45(6):580-5
23715323
Am J Respir Crit Care Med. 2015 Mar 1;191(5):530-7
25562107
Lancet Oncol. 2010 Feb;11(2):121-8
20022809
Cancer Res. 2006 Oct 1;66(19):9408-19
17018595
PLoS Genet. 2010 Aug 05;6(8):null
20700438
Nat Genet. 2011 Jun;43(6):513-8
21614091
J Clin Oncol. 2008 Jun 1;26(16):2745-53
18509184
Clin Pharmacol Ther. 2012 Jul;92 (1):112-7
22617227
Lancet Oncol. 2011 Aug;12(8):735-42
21783417
N Engl J Med. 2009 Sep 3;361(10):947-57
19692680
Nat Rev Genet. 2013 Jan;14(1):23-34
23183705
J Clin Oncol. 2011 May 20;29(15):2121-7
21482992