SNP (–617C>A) in ARE-Like Loci of the NRF2 Gene: A New Biomarker for Prognosis of Lung Adenocarcinoma in Japanese Non-Smoking Women

<div><p>Purpose</p><p>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 <i>NRF2</i> gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the <i>NRF2</i> gene as a prognostic biomarker in lung cancer.</p><p>Experimental Design</p><p>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 <i>NRF2</i> gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the <i>NRF2</i> gene and patients’ overall survival.</p><p>Results</p><p>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 <i>NRF2</i> SNP homozygous alleles (c.–617A/A) and the 309T (WT) allele in the <i>MDM2</i> gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021).</p><p>Conclusion</p><p>SNP homozygous (c.–617A/A) alleles in the <i>NRF2</i> gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.</p></div

Frequencies of wild type (–617C) and SNP (–617A) alleles in the <i>NRF2</i> gene among different ethnic groups.

<p>N, the number of subjects.</p>*<p>1000 Genomes. <a href="http://browser.1000genomes.org/Homo_sapiens/Variation/Population?db=corer=2" target="_blank">http://browser.1000genomes.org/Homo_sapiens/Variation/Population?db=corer=2</a>∶178129537–178130537;v = rs6721961;vdb = variation;vf = 4574214.</p

Clinicopathological profiling of 24 patients harboring homozygous SNP alleles (–617A/A) in the <i>NRF2</i> gene.

<p>Abbreviation: Ad, adenocarcinoma; Mix, adenocarcinoma and squamous cell carcinoma; Ple, pleomorphic carcinoma; Sq, squamous cell carcinoma; F, female; M, male; Wt, wild type.</p>†<p>Patient (case 5) died because of primary pancreatic cancer.</p

Classification of primary lung cancer patients with respect to <i>NRF2</i> genotypes, smoking behavior, adenocarcinoma, and gender.

*<p><i>P</i>-values were calculated by Fisher’s exact test.</p><p>Abbreviation: M, male; F, female.</p

Kaplan-Meier plots showing the overall survival of patients harboring the WT homozygote (–617C/C), WT/SNP heterozygote (–617C/A), or SNP homozygote (–617A/A) in the <i>NRF2</i> gene.

<p>Patients with p-stages I to IV (<b>A</b>) and p-stage I only NSCLC (<b>B</b>). The number of patients at times 0, 500, 1000, or 1500 days after surgical operation is described along with genotypes of the <i>NRF2</i> gene.</p