WRN promoter CpG island hypermethylation does not predict more favorable outcomes for patients with metastatic colorectal cancer treated with irinotecan-based therapy

Linda J W Bosch, Yanxin Luo, Victoria V. Lao, Petur Snaebjornsson, Geert Trooskens, Ilse Vlassenbroeck, Sandra Mongera, Weiliang Tang, Piri Welcsh, James G. Herman, Miriam Koopman, Iris D. Nagtegaal, Cornelis J A Punt, Wim Van Criekinge, Gerrit A. Meijer, Raymond J. Monnat, Beatriz Carvalho, William M. Grady

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: WRN promoter CpG island hypermethylation in colorectal cancer 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 patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based therapy. Experimental 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 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 colorectal cancer cell lines and in primary colorectal cancer and were largely independent ofWRNmethylation status. Patients with methylated WRN colorectal cancer had a shorter OS compared with patients who had unmethylatedWRNcolorectal cancer (HR = 1.6; 95% confidence interval [CI], 1.2-2.2; P = 0.003). Patients with unmethylated WRN showed a significantly longer PFS when treated with CAPIRI compared with capecitabine alone (HR = 0.48; 95%CI, 0.32-0.70; P = 0.0001). In contrast, patients did not benefit fromadding irinotecan to capecitabine whenWRN was methylated (HR = 1.1; 95% CI, 0.69-1.77; P = 0.7). Conclusions: WRN expression is largely independent of WRN promoter hypermethylation in colorectal cancer. Moreover, we could not validate the previous finding that WRN promoter hypermethylation predicts improved clinical outcomes of mCRC treated with irinotecan-based therapy and found instead the opposite result. Clin Cancer Res; 22(18); 4612-22.

Original languageEnglish (US)
Pages (from-to)4612-4622
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'WRN promoter CpG island hypermethylation does not predict more favorable outcomes for patients with metastatic colorectal cancer treated with irinotecan-based therapy'. Together they form a unique fingerprint.

Cite this