CHFR Promoter Methylation Indicates Poor Prognosis in Stage II Microsatellite Stable Colorectal Cancer

Abstract

Purpose: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here, we examine the prognostic impact of promoter methylation in patients with CRC treated with surgery alone in the context of microsatellite instability (MSI), BRAF and KRAS mutations.Experimental Methods: One hundred and seventy-three CRCs were analyzed for promoter methylation of 19 tumor suppressor and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations.Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 [CL1, 57% (98/173) of CRCs], cluster 2 [CL2, 25% (43/173) of CRCs], and cluster 3 [CL3, 18% (32/173) of CRCs]. CL3 had the highest methylation index (0.25, 0.49, and 0.69, respectively, P ¼ <0.01) and was strongly associated with CIMP (P < 0.01). Subgroup analysis for tumor stage, MSI, and BRAF status showed no statistically significant differences in survival between CL1, CL2, and CL3 nor between CIMP and non-CIMP CRCs. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, microsatellite stability (MSS), BRAF wild-type (WT) CRCs: multivariate Cox proportional HR ¼ 3.89 [95% confidence interval (CI), 1.58-9.60, P < 0.01; n ¼ 66] and HR ¼ 2.11 (95% CI, 0.95-4.69, P ¼ 0.068, n ¼ 136) in a second independent population-based study.Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF WT CRCs. Clin Cancer Res; 20(12); 3261-71. Ó2014 AACR.

Different prognostic effect of CpG island methylation according to sex in colorectal cancer patients treated with adjuvant FOLFOX

“…We have recently reported that concurrent methylation in NEUROG1 and CDKN2A (p16) is associated with higher recurrence in colorectal cancer patients whereas CIMP classification based on the number of methylated markers was not [ 4 ]. Importance of individual gene methylation such as CHFR , MGMT , and SHISA3 has also been shown in other studies [ 6 , 10 , 11 ].…”

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

“…Pelosof et al (18) suggested therefore that docetaxel should be used for the treatment of patients with colorectal cancer who presented with CHFR promoter methylation. Cleven et al (19) reported that hypermethylation of CHFR in patients with colorectal cancer indicates poor prognosis of stage ll colorectal cancer. Subsequently, CHFR methylation may serve for selecting chemotherapy agents for cancers of the digestive tract system, and could be considered a putative prognostic indicator in cancer therapy.…”

“…Hypermethylation of the promoter regions of the cysteine dioxygenase 1 (CDO1), tachykinin precursor 1 (TAC1) and checkpoint with forkhead and ring finger domains (CHFR) genes has been reported in various types of cancer (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), including colorectal cancer (12,15,19). The risk factors for pancreatic cancer are similar to those for colorectal cancer, and include cigarette smoking and alcohol consumption (22,23).…”

Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients

“…Recently developed molecular classification systems will likely improve the stratification and treatment of CRC patients [7, 15–18]. In a previous study of the largest cohort of duodenal adenocarcinoma patients to date, we classified tumors into four subtypes based on the combination of CIMP and MLH1 methylation status.…”