Omics Science Center, RIKEN Yokohama Institute, Yokohama, Japan ; Department of Clinical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
PLoS One. 2013 Sep 11;8(9):e73794. doi: 10.1371/journal.pone.0073794. eCollection 2013.
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.
转录因子 NRF2 在保护正常细胞免受外部毒性挑战和氧化应激方面发挥着关键作用，而它也使癌细胞能够抵抗抗癌药物。目前，关于 NRF2 基因的遗传多态性及其临床相关性的信息很少。我们旨在研究 NRF2 基因的单核苷酸多态性作为肺癌的预后生物标志物。
我们从 387 名日本原发性肺癌患者中制备基因组 DNA 样本，并通过我们在本研究中开发的快速基因检测方法检测人 NRF2 基因 ARE 样位点的 SNP（c.-617C>A; rs6721961）。然后，我们分析了 NRF2 基因中的 SNP 与患者总生存期之间的关联。
野生型（WT）纯合子（c.-617C/C）、SNP 杂合子（c.-617C/A）和 SNP 纯合子（c.-617A/A）患者分别为 216 例（55.8%）、147 例（38.0%）和 24 例（6.2%）。多变量逻辑回归模型显示 SNP 纯合子（c.-617A/A）与性别显著相关。女性患者 SNP 纯合子的频率明显高于男性（10.8%女性 vs 2.7%男性），与女性非吸烟者的腺癌有关。有趣的是，携带 NRF2 SNP 纯合子等位基因（c.-617A/A）和 MDM2 基因中的 309T（WT）等位基因的肺癌患者在手术后 1700 多天后表现出显著的生存（对数秩检验，p=0.021）。
NRF2 基因中的 SNP 纯合子（c.-617A/A）等位基因与女性非吸烟者的腺癌有关，可作为评估肺腺癌患者总生存期的预后生物标志物。
