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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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
Pages (from-to)4612-4622
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number18
DOIs
Publication statusPublished - 15 Sept 2016

Bibliographical note

Funding Information:
Support for these studies was provided by the NIH (RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852), and a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (to W.M. Grady). V.V. Laowas supported by ACS fellowship PF-11-086-01-TBG; 2T32DK007742-16; ASCRS GSRRIG; and NIH NCI F32CA1591555-01. L.J.W. Bosch was supported by Dutch Cancer Society (KWF Fellowship VU 2013-5885). Support for these studies was also provided by National Natural Science Foundation of China (81201920, 81472257; to Y. Luo). Parts of this study were performed within the framework of CTMM, the Center for Translational Molecular Medicine, DeCoDe project (grant 03O-101), and the Dutch Colorectal Cancer Group (DCCG). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
©2016 American Association for Cancer Research.

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