Yonsei Med J.  2018 Jul;59(5):588-594. 10.3349/ymj.2018.59.5.588.

CpG Island Methylator Phenotype and Methylation of Wnt Pathway Genes Together Predict Survival in Patients with Colorectal Cancer

• Kim SH
• Park KH
• Shin SJ
• Lee KY
• Kim TI
• Kim NK
• Rha SY
• Ahn JB

• KMID: 2412649
• DOI: http://doi.org/10.3349/ymj.2018.59.5.588

Abstract

PURPOSE
Dysregulation of the Wnt pathway is a crucial step in the tumorigenesis of colorectal cancer (CRC). This study aimed to determine whether DNA methylation of Wnt pathway genes helps predict treatment response and survival in patients with metastatic or recurrent CRC.
MATERIALS AND METHODS
We retrospectively collected primary tumor tissues from 194 patients with metastatic or recurrent CRC. Pyrosequencing was used to examine the methylation of 10 CpG island loci in DNA extracted from formalin-fixed paraffin-embedded specimens. To elucidate the predictive role of DNA methylation markers, Kaplan-Meier survival estimation and Cox regression were performed for progression-free survival and overall survival (OS).
RESULTS
The methylation frequencies of the 10 genes analyzed (p16, p14, MINT1, MINT2, MINT31, hMLH1, DKK3, WNT5A, AXIN2, and TFAP2E) were 47.9%, 10.8%, 21.1%, 16.0%, 20.6%, 0.5%, 53.1%, 32.0%, 2.6%, and 2.1%, respectively. We divided patients into three groups based on the number of methylated genes (group 1, no methylation n=38; group 2, 1-2 methylations n=92; group 3, 3 or more methylations n=64). Among patients treated with palliative chemotherapy (n=167), median OSs of groups 1, 2, and 3 were 39.1, 39.7, and 29.1 months, respectively (log rank p=0.013). After adjustment, number of methylations was identified as an independent poor prognostic factor (0-2 methylated vs. ≥3 methylated: hazard ratio, 1.72; 95% confidence interval, 1.16-2.56, p=0.007).
CONCLUSION
This study suggests that methylation of Wnt pathway genes, in addition to known CpG island methylator phenotype markers, may help predict treatment outcome and survival in patients with CRC.

Keyword

Colorectal carcinoma; CpG island methylator phenotype; DNA methylation; Wnt pathway

MeSH Terms

Carcinogenesis
Colorectal Neoplasms*
CpG Islands*
Disease-Free Survival
DNA
DNA Methylation
Drug Therapy
Humans
Methylation*
Phenotype*
Retrospective Studies
Treatment Outcome
Wnt Signaling Pathway*
DNA

Figure

• 

  Fig. 1 Distribution of mutations and methylation in our patients. Each bar represents individual mutations (light blue) and methylations (dark blue). CIMP is denoted by an orange bar. CIMP-positive tumors had more frequent KRAS or BRAF mutation than CIMP negative tumors. CIMP, CpG island methylator phenotype.

• 

  Fig. 2 Bar chart showing the best objective response of first-line chemotherapy in each group. ORR was higher in group 1 (66.7%) than in group 2 (46.3%) or 3 (43.2%). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UA, unavailable, ORR, objective response rate.

• 

  Fig. 3 Overall survival according to CpG island phenotype (A) and the number of methylations (B). CIMP, CpG island methylator phenotype.

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