SNP (-617C>A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma in Japanese non-smoking women

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 th...

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Published in:PloS one 2013-09, Vol.8 (9), p.e73794
Main Authors: Okano, Yasuko, Nezu, Uru, Enokida, Yasuaki, Lee, Ming Ta Michael, Kinoshita, Hiroko, Lezhava, Alexander, Hayashizaki, Yoshihide, Morita, Satoshi, Taguri, Masataka, Ichikawa, Yasushi, Kaneko, Takeshi, Natsumeda, Yutaka, Yokose, Tomoyuki, Nakayama, Haruhiko, Miyagi, Yohei, Ishikawa, Toshihisa
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - diagnosis
Adenocarcinoma - ethnology
Adenocarcinoma - genetics
Alleles
Analysis
Antineoplastic drugs
Antitumor agents
Asian Continental Ancestry Group - genetics
Biomarkers
Biomarkers, Tumor - genetics
Cancer
Cancer diagnosis
Cancer genetics
Cancer treatment
Cell growth
Deoxyribonucleic acid
DNA
Drug resistance
Drugs
Enzymes
Epidermal growth factor
Experimental design
Female
Gene expression
Gene Frequency
Genes
Genetic aspects
Genetic screening
Genetic testing
Genetic Testing - methods
Genotype
Humans
Japan
Kaplan-Meier Estimate
Loci
Logistic Models
Lung cancer
Lung diseases
Lung Neoplasms - diagnosis
Lung Neoplasms - ethnology
Lung Neoplasms - genetics
Male
Males
MDM2 protein
Medical prognosis
Medicine
Middle Aged
Multivariate Analysis
Mutation
NF-E2-Related Factor 2 - genetics
NRF2 protein
Oxidation resistance
Oxidative stress
Patients
Polymorphism, Single Nucleotide
Prognosis
Proteins
Proto-Oncogene Proteins c-mdm2 - genetics
Regression analysis
Regression models
Science
Sex Factors
Single nucleotide polymorphisms
Single-nucleotide polymorphism
Smoking
Surgery
Survival
Test procedures
Thoracic surgery
Transcription (Genetics)
Transcription factors
University graduates
Women's health
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Description
Summary: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. 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. 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). 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0073794