Abstract 670: DNA methylation pattern predicts treatment response and survival in patients with metastatic or recurrent colorectal cancer.
Authors: Kim Se Hyun , Park Kyu Hyun , Shin Sang Joon , Lee Kang Young , Kim Tae Il , Kim Nam Kyu , Rha Sun Young , Roh Jae Kyung , Ahn Joong Bae 
Published: August 2014

Background: The epigenetic changes such as DNA methylation affect various steps in tumorigenesis of colorectal carcinoma. The aim of this study was to investigate whether DNA methylation pattern was associated with chemotherapeutic response and survival in patients with metastatic or recurrent colorectal cancer.

Patients and method: We retrospectively collected tumor tissues of primary site from 236 patients with metastatic or recurrent colorectal cancer (mCRC). Pyrosequencing was used to examine the methylation of 7 CpG island loci (p16, p14, MINT1, MINT2, MINT31, hMLH1, DKK3) 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 time to progression (TTP) and overall survival (OS). KRAS and BRAF mutations were also analyzed.

Result: The methylation frequencies of the 7 genes analyzed were 45.8% for p16, 14.0% for p14, 22.0% for MINT1, 14.4% for MINT2, 19.9% for MINT31, 2.1% for MLH1, and 33.9% for DKK3. As for mutation status, 28.8% (68 of 229) tumors harbored KRAS mutation and 2.5% (6 of 125) tumors harbored BRAF mutation. Both mutations were mutually exclusive. We devided patients into three groups on the basis of the number of methylated genes (group 1, 0∼1 methylation n=117; group 2, 2∼4 methylation n=73; group 3, 5-7 methylation n=9). Median OS of group 3 was significantly shorter than other groups (median OS 38.1m in group1 vs 19.4m in group 3, log rank P=0.003; median OS 38.0m in group2 vs 19.4m in group3, log rank P=0.012). In 129 patients with measurable lesions, group 3 (n=6) showed a trend toward lower disease control rate (DCR=66.7%) and shortend TTP (median 3.5m) than group 1 (n=76, 86.8%, 7.6m) or group 2 (n=47, 80.9%, 6.6m). In multivariate analysis for OS, initial tumor stage (AJCC 1-3 vs 4: HR=2.67; 95%CI, 1.82-3.93, P &lt;0.0001), tumor differentiation (well/moderate vs poor/mucinous: HR=2.18; 95%CI, 1.41-3.37, P &lt;0.0001), resectability (resectable vs unresectable: HR=2.55; 95%CI, 1.54-4.22, P &lt;0.0001), and number of methylation (0-4 methylated vs 5-7 methylated: HR=2.26; 95%CI, 1.11-4.60, P=0.025) were independent prognostic factors.

Conclusion: This study suggests that DNA methylation status may predict treatment outcome and survival in patients with metastatic or recurrent colorectal carcinoma.

Citation Format: Se Hyun Kim, Kyu Hyun Park, Sang Joon Shin, Kang Young Lee, Tae Il Kim, Nam Kyu Kim, Sun Young Rha, Jae Kyung Roh, Joong Bae Ahn. DNA methylation pattern predicts treatment response and survival in patients with metastatic or recurrent colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 670. doi:10.1158/1538-7445.AM2013-670