Abstract 316: Keap1 and Nrf2 genetic mutations and polymorphisms: Associations with clinical outcome in endometrial cancer

Abstract

Abstract Background: Constitutive activation and increased expression of Nrf2 as a result of oncogenic mutations or other endogenous factors that cause derepression of Nrf2 by its cytosolic inhibitor, Keap1, contribute to tumor resistance to adjuvant treatment. As endometrial cancer generally has a lower response rate to adjuvant treatment, Keap1 and Nrf2 genes were sequenced to investigate their roles in endometrial cancer. Materials and Methods: Tumor specimens from 105 individuals with endometrioid endometrial adenocarcinoma (Type I endometrial cancer) were sequenced. The specimens comprised 44 well-differentiated (FIGO grade 1), 38 moderately differentiated (FIGO grade 2) and 23 poorly differentiated (FIGO grade 3) tumors. Statistical analyses using the Fisher's exact test, Pearson's Chi-square test and Cox proportional hazards model were used to investigate the association of genetic mutations and haplotypes with patients’ annotated clinicopathologic characteristics. Results: A total of ten novel Keap1 mutations were found in nine individuals, and two novel Nrf2 mutations were found in three individuals. One patient had two simultaneous Keap1 mutations, whereas two patients had the same type of Nrf2 genetic mutation. Two single nucleotide polymorphisms, rs1048290 and rs11545829 were found in high frequency in the present cohort. The non-synonymous genetic mutations and rs11545829 were not associated with patients’ clinicopathologic characteristics. In the adjuvant treatment subgroup, the rs1048290 c.1413C/G genotype was significantly associated with a better progression-free survival (hazard ratio, 0.25; 95% confidence interval [CI], 0.068 to 0.94; P=0.041). On multivariate analysis, rs1048290 was an independent prognostic factor for progression-free survival (hazard ratio, 0.16; 95% CI, 0.036 to 0.69; P=0.014). Conclusion: Keap1 single nucleotide polymorphism rs1048290 may be a potential biomarker that enables individualized therapy using cytotoxic adjuvant treatment in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2011-316