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

Purpose: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations betweenmethylation and other factors affecting survival such as genetic alterations anduse 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 promotermethylation of 19 tumor suppressor andDNA repair genes, the CpG islandmethylator 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, P1⁄4 <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-CIMPCRCs. Analyzing genes separately revealed thatCHFR promotermethylation was associated with a poor prognosis in stage II, microsatellite stability (MSS), BRAFwild-type (WT) CRCs: multivariate Cox proportional HR 1⁄4 3.89 [95% confidence interval (CI), 1.58–9.60, P < 0.01; n1⁄4 66] and HR 1⁄4 2.11 (95% CI, 0.95–4.69, P 1⁄4 0.068, n 1⁄4 136) 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, BRAFWTCRCs. Clin Cancer Res; 20(12); 3261–71. 2014 AACR.