Association of Keap1 and Nrf2 Genetic Mutations and Polymorphisms With Endometrioid Endometrial Adenocarcinoma Survival

Abstract

Dysregulation of Kelch-like erythroid cell-derived protein with CNC homology-associating protein (Keap)-nuclear factor E2-related factor 2 (Nrf2) homeostasis owing to oncogenic mutations or to endogenous alteration of protein expression levels is implicated in tumor resistance to adjuvant treatment. To understand the role of Keap1 and Nrf2 in endometrial cancer, we performed DNA sequencing of tumors and noted the relation of the DNA sequence with annotated clinicopathologic data. We sequenced the Keap1 and Nrf2 genes in 105 tumor specimens. Associations of genetic mutations and polymorphisms with the patients' clinicopathologic characteristics were evaluated. We detected 9 patients with Keap1 mutations and 3 patients with Nrf2 mutations. No patient had both Keap1 and Nrf2 mutations. We found 2 single nucleotide polymorphisms within the coding region of Keap1 - rs1048290 (c. 1413C>G) and rs11545829 (c. 1611C>T) that displayed high heterogeneity in our cohort. The c. 1413C>G polymorphism is significantly associated with progression-free survival by multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.036-0.69; P = 0.014). The presence of Keap1 or Nrf2 mutations and c. 1611C>T are not associated with the clinical outcome of the patients. Mutations impairing Keap1-Nrf2 interaction are relatively common in endometrial cancer (12 [11.4%] of 105). Keap1 single nucleotide polymorphism rs1048290 may be a novel independent prognostic marker for patients with endometrial cancer receiving adjuvant treatment. Therefore, genotyping patients for this Keap1 polymorphism will help identify patient subgroups more likely to benefit from standard adjuvant therapy.