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BMC Cancer. 2019 Nov 21;19(1):1137. doi: 10.1186/s12885-019-6347-0.

Nrf2 gene mutation and single nucleotide polymorphism rs6721961 of the Nrf2 promoter region in renal cell cancer.

Author information

1
Department of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.
2
Department of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan. kamait@dokkyomed.ac.jp.
3
Department of Molecular and Cell Biology, Dokkyo Medical University, Mibu, Tochigi, Japan.
4
Division of Field Application, Life Technologies, Tokyo, Japan.

Abstract

BACKGROUND:

Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in cell proliferation by promotion of metabolic activity. It is also the major regulator of antioxidants and has a pivotal role in tumor cell proliferation and resistance to chemotherapy. Accordingly, we investigated the role of Nrf2 in renal cell carcinoma (RCC).

METHODS:

In 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression.

RESULTS:

Targeted next-generation sequencing revealed that five tumors had SNPs of Nrf2 associated with amino acid sequence variation, while 11 tumors had SNPs of Kelch-like ECH-associated protein 1 gene, 35 had SNPs of von Hippel-Lindau gene, and none had SNPs of fumarate hydratase gene. The three genotypes of rs6721961 showed the following frequencies: 60% for C/C, 34% for C/A, and 6% for A/A. Nrf2 mutation and the C/A or A/A genotypes were significantly associated with increased Nrf2 protein expression (p = 0.0184 and p = 0.0005, respectively). When the primary tumor showed Nrf2 gene mutation, the C/A or A/A genotype, or elevated Nrf2 protein expression, the response of metastases to vascular endothelial growth factor-targeting therapy was significantly worse (p = 0.0142, p = 0.0018, and p <  0.0001, respectively), and overall survival was significantly reduced (p = 0.0343, p = 0.0421, and p <  0.0001, respectively). Elevated Nrf2 protein expression was also associated with shorter survival according to multivariate Cox proportional analysis.

CONCLUSION:

These findings suggest an associated between progression of RCC and Nrf2 signaling.

KEYWORDS:

Kelch-like ECH-associated protein 1 (Keap1); Nuclear factor erythroid 2–related factor 2 (Nrf2); Renal cell carcinoma; Single nucleotide polymorphism

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