PURPOSE: WRN promoter CpG island hypermethylation in colorectal cancer (CRC) has been reported to increase sensitivity to irinotecan-based therapies. We aimed to characterize methylation of the WRN promoter; determine the effect of WRN promoter hypermethylation upon expression; and validate a previous report that WRN promoter hypermethylation predicts improved outcomes for metastatic colorectal cancer (mCRC) patients treated with irinotecan-based therapy. DESIGN: WRN methylation status was assessed using methylation-specific PCR and bisulfite sequencing assays. WRN expression was determined using qRT-PCR and Western blotting. WRN methylation status was correlated with overall survival (OS) and progression-free survival (PFS) in 183 patients with mCRC. Among these patients 90 received capecitabine monotherapy (CAP) as first line therapy and 93 received capecitabine plus irinotecan (CAPIRI) therapy as part of the CAIRO Phase III clinical trial. RESULTS: WRN mRNA and WRN protein expression levels were low in CRC cell lines and in primary CRC, and were largely independent of WRN methylation status. Patients with methylated WRN CRC had a shorter OS compared to patients who had unmethylated WRN CRC (hazard ratio [HR]=1.6 (95%CI1.2-2.2), p=0.003). Patients with unmethylated WRN showed a significantly longer PFS when treated with CAPIRI compared to CAP alone (HR=0.48 (95%CI 0.32-0.70), p=0.0001). In contrast, patients did not benefit from adding irinotecan to CAP when WRN was methylated (HR=1.1 (95%CI 0.69-1.77), p=0.7). CONCLUSION: WRN expression is largely independent of WRN promoter hypermethylation in CRC. Moreover, we could not validate previous finding that WRN promoter hypermethylation predicts improved clinical outcomes of mCRC treated with irinotecan-based therapy.
- Received November 6, 2015.
- Revision received March 21, 2016.
- Accepted March 26, 2016.
- Copyright ©2016, American Association for Cancer Research.