br Conflict of interest statement br Dr
Conflict of interest statement
Dr. Matei reports personal fees from Astra Zeneca, Genentech/Roche, Tesaro, Astex, Clovis, and the European commission that Influenza Hemagglutinin HA Peptide are outside the submitted work. All other authors report no conflicts of interest.
Conceptualization: Goodman, Seagle, Strauss. Formal Analysis and
Methodology: Goodman, Strauss, Hatoum, Seagle. Writing – Original
Draft: Goodman, Hatoum; Writing – Review and Editing: Goodman,
Hatoum, Seagle, Barber, Matei, Strauss. Project Administration: Hatoum,
Donnelly, Barber, Matei, Shahabi, Strauss. Supervision: Strauss, Shahabi.
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Association of CHFR Promoter Methylation with Treatment Outcomes of Irinotecan-Based Chemotherapy in Metastatic Colorectal Cancer
* Center for Colorectal Cancer, National Cancer Center, Goyang, Korea; †Precision Medicine Branch, Division of Precision Medicine, Research Institute of National Cancer Center, Goyang, Korea; ‡Translational Research Branch, Division of Translational Science, Research Institute of National Cancer Center, Goyang, Korea; §Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research Institute of National Cancer Center, Goyang, Korea
Aberrant promoter methylation plays a vital role in colorectal carcinogenesis. However, its role in treatment responses is unclear, especially for metastatic disease. Here, we investigated the association between promoter methylation and treatment outcomes of irinotecan-based chemotherapy in 102 patients with metastatic colorectal cancer. Promoter methylation was examined by methylation-specific polymerase chain reaction for three loci (CHFR, WRN, and SULF2) associated with chemotherapy response and five CpG island methylator phenotype (CIMP)–specific markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1). Association between CHFR methylation and in vitro sensitivity to irinotecan was also evaluated. Promoter methylation of CHFR, WRN, and SULF2 was identified in 16 (15.7%), 24 (23.5%), and 33 (32.4%)
patients, respectively. CIMP status was positive in 22 (21.6%) patients. CHFR methylation was associated with a significantly longer time to progression (TTP) (median: 8.77 vs. 4.43 months, P = .019), with trends favoring higher overall survival (OS) (median: 22.83 vs. 20.17 months, P = .300) and response rates (31.3% vs. 17.4%, P = .300). For patients with unmethylated CHFR, TTP (median: 5.60 vs. 3.53, P = .020) and OS (median: 20.57 vs. 9.23, P = .006) were significantly different according to CIMP status. Colorectal cancer cell lines with CHFR methylation demonstrated increased sensitivity to irinotecan. Both CHFR overexpression and combination with 5-aza-2′-deoxycytidine reversed irinotecan sensitivity in CHFR-methylated cell lines, whereas CHFR knockdown in unmethylated cells restored sensitivity to irinotecan. These data suggest that CHFR methylation may be associated with favorable treatment outcomes of irinotecan-based chemotherapy in patients with metastatic colorectal cancer.