Hypermethylation of the KEAP1 gene in colorectal cancer and association with disease progression.

Abstract

e14655 Background: Aberrant methylation of the KEAP1 (Kelch-like ECH-associated protein 1) gene promoter is emerging as a main mechanism of dysregulation of the NrF2 (nuclear factor-erythroid 2-related factor 2 ) which plays a pivotal role in the cellular response to oxidative stress. Under basal conditions, Nrf2 is retained in the cytoplasm by the binding with Keap1 and it is maintained at a reduced level by the Keap1-dependent ubiquitination and proteasomal degradation systems. Reduced Keap1 expression by promoter aberrant methylation allows Nrf2 to translocate in the nucleus and to activate the detoxification pathway leading ultimately to drug resistance. Methods: We determined KEAP1 promoter methylation status in 50 metastatic colorectal cancer (CRC) and 9 normal colonic mucosa samples by using quantitative methylation specific PCR in real time (QMSP). The median age of the patients cohort was 65 (IQR 57-74) years. At diagnosis 12 patients were staged Duke D and 38 were staged as Duke C. As first line treatment the FOLFOX or FOLFIRI therapeutical schemes were used. Results: Methylation was detected in 20 out of 50 CRC (40%) and methylation levels were significantly higher in tumour samples (Median 0.65, IQR 0-8.28) as compared with normal colonic mucosa (Median 0, IQR 0-0.08) (P=0.03). Tumours from patients who experieced disease progression had significantly higher methylation levels (Median 0.53; IQR 0-7.61) as compared with patients showing partial response (Median 0, IQR 0-2.21) or disease stability (Median 0, IQR 0-0) (P=0.03 Kruskall Wallis Test). Conclusions: Our results suggest that Keap1 aberrant methylation is a frequent event in colorectal cancer and is associated with response to chemotherapeutical treatments.