title: SNP (-617C>A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma in Japanese non-smoking women.
abstract: OBJECTIVE
  The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the NRF2 gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the NRF2 gene as a prognostic biomarker in lung cancer.
  
  
  METHODS
  We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.-617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the NRF2 gene and patients' overall survival.
  
  
  RESULTS
  Patients harboring wild-type (WT) homozygous (c.-617C/C), SNP heterozygous (c.-617C/A), and SNP homozygous (c.-617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.-617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying NRF2 SNP homozygous alleles (c.-617A/A) and the 309T (WT) allele in the MDM2 gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021).
  
  
  CONCLUSIONS
  SNP homozygous (c.-617A/A) alleles in the NRF2 gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.
authors.affiliation: Omics Science Center, RIKEN Yokohama Institute, Yokohama, Japan ; Department of Clinical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Okano
authors.forename: Uru
authors.initials: U
authors.lastname: Nezu
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Enokida
authors.forename: Ming Ta Michael
authors.initials: MT
authors.lastname: Lee
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Alexander
authors.initials: A
authors.lastname: Lezhava
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Masataka
authors.initials: M
authors.lastname: Taguri
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Natsumeda
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yokose
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Nakayama
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D000483:Alleles; D044466:Asian People / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008175:Lung Neoplasms / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012737:Sex Factors; D012907:Smoking
chemical_list: D014408:Biomarkers, Tumor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
references.citation: Nat Methods. 2007 Mar;4(3):257-62
references.pmid: 17322893
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3410-5
references.pmid: 11248092
references.citation: FASEB J. 2007 Jul;21(9):2237-46
references.pmid: 17384144
references.citation: Histopathology. 2012 May;60(6):943-52
references.pmid: 22348534
references.citation: Free Radic Biol Med. 2005 Feb 1;38(3):325-43
references.pmid: 15629862
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
references.pmid: 15329413
references.citation: Blood. 1996 Jun 15;87(12):5074-84
references.pmid: 8652820
references.citation: Genes Cells. 2011 Feb;16(2):123-40
references.pmid: 21251164
references.citation: J Biol Chem. 2000 May 26;275(21):16023-9
references.pmid: 10821856
references.citation: Clin Cancer Res. 2009 May 15;15(10):3423-32
references.pmid: 19417020
references.citation: Br J Cancer. 2006 Oct 23;95(8):1070-5
references.pmid: 17047654
references.citation: Mod Pathol. 2008 May;21 Suppl 2:S16-22
references.pmid: 18437168
references.citation: Cell. 2004 Nov 24;119(5):591-602
references.pmid: 15550242
references.citation: Oncotarget. 2012 Nov;3(11):1272-83
references.pmid: 23174755
references.citation: J Mol Diagn. 2006 Sep;8(4):504-12
references.pmid: 16931592
references.citation: Mol Cell Biol. 1995 Aug;15(8):4184-93
references.pmid: 7623813
references.citation: Clin Cancer Res. 2007 Oct 1;13(19):5763-8
references.pmid: 17908966
references.citation: Mol Cancer Ther. 2010 Aug;9(8):2365-76
references.pmid: 20682644
references.citation: Science. 2006 Oct 13;314(5797):268-74
references.pmid: 16959974
references.citation: Pharmacol Res. 2008 Nov-Dec;58(5-6):262-70
references.pmid: 18838122
references.citation: Mol Cell Biol. 2002 May;22(9):2883-92
references.pmid: 11940647
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9926-30
references.pmid: 7937919
references.citation: Cell Mol Life Sci. 1999 Jan;55(1):96-107
references.pmid: 10065155
references.citation: Biochem Biophys Res Commun. 2004 Aug 13;321(1):72-9
references.pmid: 15358217
references.citation: Science. 2004 Jun 4;304(5676):1497-500
references.pmid: 15118125
references.citation: Biopharm Drug Dispos. 2009 Oct;30(7):345-55
references.pmid: 19725016
references.citation: Cancer. 2008 Aug 15;113(4):799-807
references.pmid: 18618574
references.citation: Nat Genet. 2012 Dec;44(12):1330-5
references.pmid: 23143601
references.citation: Drug Metab Pharmacokinet. 2006 Dec;21(6):437-57
references.pmid: 17220560
references.citation: Genes Dev. 1999 Jan 1;13(1):76-86
references.pmid: 9887101
references.citation: Hum Hered. 2006;61(1):27-30
references.pmid: 16534213
references.citation: J Biol Chem. 2009 May 15;284(20):13291-5
references.pmid: 19182219
references.citation: Hum Genet. 1997 Jul;100(1):145-7
references.pmid: 9225984
references.citation: J Pharmacol Exp Ther. 2006 Jun;317(3):1114-24
references.pmid: 16489126
references.citation: Drug Metab Dispos. 2006 Apr;34(4):524-33
references.pmid: 16415123
references.citation: Hum Genet. 2012 Jul;131(7):1197-203
references.pmid: 22367405
references.citation: Cancer Cell. 2012 Jul 10;22(1):66-79
references.pmid: 22789539
references.citation: Adv Enzyme Regul. 2006;46:113-40
references.pmid: 16887173
references.citation: PLoS One. 2013;8(4):e60151
references.pmid: 23565197
references.citation: Trends Mol Med. 2004 Nov;10(11):549-57
references.pmid: 15519281
references.citation: Arch Biochem Biophys. 2011 Mar 15;507(2):356-64
references.pmid: 21211512
references.citation: Oncogene. 2012 Nov 8;31(45):4768-77
references.pmid: 22249257
references.citation: N Engl J Med. 2004 May 20;350(21):2129-39
references.pmid: 15118073
references.citation: Methods Mol Biol. 2013;1015:55-69
references.pmid: 23824848
references.citation: Clin Cancer Res. 2010 Jul 15;16(14):3743-53
references.pmid: 20534738
references.citation: Nat Rev Immunol. 2009 May;9(5):377-84
references.pmid: 19330016
references.citation: PLoS Genet. 2010 Aug 05;6(8):
references.pmid: 20700438
references.citation: J Clin Oncol. 2011 Jul 20;29(21):2866-74
references.pmid: 21670455
references.citation: Trends Biochem Sci. 2009 Apr;34(4):176-88
references.pmid: 19321346
references.citation: Eur J Biochem. 1989 Feb 15;179(3):557-63
references.pmid: 2537723
references.citation: J Exp Ther Oncol. 2007;6(4):335-48
references.pmid: 18038766
references.citation: Nat Rev Cancer. 2012 Jul 19;12(8):564-71
references.pmid: 22810811
references.citation: Clin Chim Acta. 2011 Jun 11;412(13-14):1249-51
references.pmid: 21420395
references.citation: J Biol Chem. 2011 Jun 10;286(23):20558-68
references.pmid: 21487020