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

PurposeThe 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.Experimental DesignWe 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.ResultsPatients 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).ConclusionSNP 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.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…At the level of gene expression, it is interesting that an allele of the SNP rs6721961 (2617C . A) located at the ARE enhancer of the human NRF2 gene abolished selfinduction of NRF2, and this correlated with remarkable survival of these cancer patients (Okano et al, 2013). Epigenetic changes due to promoter hypermethylation of three CpG sites of KEAP1 have been described in lung tumors, resulting in consequent NRF2 activation that could be reversed by 5-aza-29-deoxycitydine treatment .…”

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

“…A SNP (rs6721961, c.-617A) in human NRF2 gene has been found related to survival rate after chemotherapies. The homozygous alleles (c.-617C) were identified to increase the binding affinity of NRF2 to AREs by 2-3-fold in 55.8% of reported Japanese patients with primary lung cancer, and this may pose the aberrant transactivation of NRF2 gene and subsequent increased protein level of downstream genes (Okano et al, 2013). These data point that NRF2-dependent chemoresistance could be considered as a therapeutic strategy on the basis of rapid genotyping method for personalized cancer treatment.…”

Association of NRF2 Polymorphism with Cholangiocarcinoma Prognosis in Thai Patients

“…The NRF2 gene polymorphisms is associated with oxidative stress-related and inflammation-related diseases, and also with some cancers (Marzec et al, 2007;Cordova et al, 2010;Bouligand et al, 2011;Hartikainen et al, 2012;Okano et al, 2013). However, the impact of NRF2 polymorphisms on CCA has not been studied to date.…”

“…Genetic polymorphism of NRF2 on several SNPs (including rs6721961 and rs2886162) were associated with breast cancer risk (Hartikainen et al, 2012). Moreover, a recent report showed that rs6721961 polymorphism is associated with female lung cancer (Okano et al, 2013). The role of SNPs in NRF2 as the modifier of NRF2 function or as a biomarker for diseases is needed further clarification.…”

“…In previous studies, an association of the polymorphism of detoxifying/metabolizing genes, CYP1A2, NAT1, NAT2, NQO1, GSTM1, and GSTO1 with the risk of CCA has been demonstrated (Honjo et al, 2005;Prawan et al, 2005;Kukongviriyapan, 2012). This study was conducted to determine the allele frequency of some NRF2 SNPs, in Thai population where frequencies of the SNPs have been reported in some populations and shown an association with pathological conditions (Hartikainen et al, 2012;Okano et al, 2013). The analysis of the SNPs in healthy subjects and CCA patients was conducted to estimate the risk for development of CCA.…”