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  • br Introduction br Colorectal cancer CRC is


    Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide [1]. Since the adoption of anti-EGFR and anti-
    Abbreviations: 5-Aza-CdR, 5-Aza-2′-deoxycytidine; CCLE, the Cancer Cell Line Encyclo-pedia; CIMP, CpG island methylator phenotype; EGFR, epidermal growth factor receptor; MSP, methylation-specific polymerase chain reaction; OS, overall survival; TCGA, The Cancer Genome Atlas; TTP, time to progression; VEGF, vascular endothelial growth factor Address all correspondence to: Prof. Hee Jin Chang, Center for Colorectal Cancer, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang 10408, South Korea or Prof. Seung Myung Dong, Molecular Epidemiology Branch, Research Institute of National Cancer Center, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang 10408, South Korea. E-mail: [email protected] 1 Equally contributed as first authors. 
    VEGF(R) 2 , 3Diaminonaphthalene in 2004, the median survival time of patients with metastatic CRC has reached 30 months [2]. However, despite the recent advances in molecular targeted therapy as well as
    2 Current address: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
    © 2018 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license ( by-nc-nd/4.0/).
    Neoplasia Vol. 21, No. 1, 2019 CHFR Promoter Methylation in Metastatic Colorectal Cancer Cha et al. 147
    immunotherapy, cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin and/or irinotecan remains the mainstay of therapy and is responsible for the majority of survival gain in metastatic CRC. Therefore, prediction of treatment response or resistance to cytotoxic chemotherapy is a highly significant and clinically relevant issue to further improve the treatment outcomes of patients with metastatic CRC.
    Irinotecan, a topoisomerase I inhibitor, is one of the major chemotherapeutic agents for metastatic CRC along with fluoropyrimi-dines and oxaliplatin. However, only 30%-40% of the patients show an objective response to irinotecan, and there is currently no established biomarker predictive of clinical benefit from irinotecan chemotherapy.
    CRC is known to have an abundance of aberrant promoter methylations [3], and methylation status has been studied for potential correlations with treatment outcomes of CRC in this regard [4–15]. Patients with the CpG island methylator phenotype (CIMP), reflecting extensive promoter methylation, were found to benefit from irinotecan chemotherapy in the adjuvant setting. A recent study also demonstrated that the treatment outcomes of metastatic CRC differed significantly according to CIMP status, adding a further prognostic role for CIMP status besides stage II and III CRC [8]. In this study, while CIMP-high metastatic CRC was associated with poorer progression-free survival and overall survival (OS) for oxaliplatin-based first-line chemotherapy, the correlation between CIMP status and treatment outcomes was less prominent for irinotecan-based second-line treatment [8]. As CIMP is one of the key molecular pathways in CRC carcinogenesis and the association between CIMP status and irinotecan response remains unclear, we aimed to further investigate the implications of CIMP in patients with metastatic CRC treated with irinotecan [16].
    In addition to CIMP status, silencing by promoter methylation in individual genes has also been suggested to induce resistance or response to irinotecan [15,17]. Checkpoint with forkhead and ring finger domains (CHFR) encodes the E3 ubiquitin-protein ligase CHFR and has been identified as a mitotic stress checkpoint and tumor suppressor gene. CHFR is frequently inactivated by promoter CpG island methylation in CRC [18–20]. CHFR methylation was associated with reduced survival in stage II and III CRC [21,22] and was suggested to be associated with enhanced sensitivity to taxanes in CRC, non–small cell lung cancer, and gastric cancer [23–27]. Although CHFR methylation has not been directly evaluated in conjunction with irinotecan therapy, recent studies have found that CHFR plays an important role in the early stage of the DNA damage response [28,29]. As CHFR is highly methylated in CRC and a well-coordinated DNA damage response pathway is required for the repair of irinotecan-induced cellular damage, we postulated that CHFR may be involved in the therapeutic response to irinotecan in addition to taxanes.
    Werner syndrome RecQ-like helicase (WRN), known as a tumor suppressor gene with exonuclease function, was reported to be frequently inactivated epigenetically and to correlate with mucinous differentiation in CRC [12,13,30]. WRN methylation has been predicted to enhance topoisomerase inhibitor activity by abrogation of its exonuclease function, and the association of WRN methylation and irinotecan response was suggested in a few studies with a relatively small number of patients with colorectal, gastric, and cervical cancers [13,31,32].