Clinicopathological and Molecular Profiles of Sporadic Microsatellite Unstable Colorectal Cancer with or without the CpG Island Methylator Phenotype (CIMP).

Shih-Ching Chang,Jeng-Kai Jiang,Pei-Ching Lin,Jen-Kou Lin,Wei-Shone Chen,Chien-Hsing Lin,Shung-Haur Yang,Hung-Hsin Lin,Chun-Chi Lin,Anna Fen-Yau Li,Shen-Chieh Huang,Yuan-Tzu Lan,Wen-Yi Liang

doi:10.3390/cancers12113487

Abstract

Simple SummaryThe 5’-C-phosphate-G-3’ island methylator phenotype (CIMP) is a phenotype of colorectal cancer associated with microsatellite instability (MSI). The aim of the present study was to analyze the CIMP phenotype and genetic mutations in MSI-high colorectal cancer. Our results demonstrated that among MSI-high colorectal cancer patients, CIMP-high tumors were associated with specific mutation profiles and clinicopahtological features compared with CIMP-low or CIMP-0 tumors, however, the CIMP status was not an independent prognostic factor.Background: The 5’-C-phosphate-G-3’ island methylator phenotype (CIMP) is a specific phenotype of colorectal cancer (CRC) associated with microsatellite instability-high (MSI-high) tumors. Methods: In this study, we determined the CIMP status using eight methylation markers in 92 MSI-high CRC patients after excluding five germline mismatch repair (MMR) gene mutations analyzed by next-generation sequencing (NGS) and confirmed by Sanger sequencing. The mutation spectra of 22 common CRC-associated genes were analyzed by NGS. Results: Of the 92 sporadic MSI-high tumors, 23 (25%) were considered CIMP-high (expressed more than 5 of 8 markers). CIMP-high tumors showed proximal colon preponderance and female predominance. The mutation profiles of CIMP-high tumors were significantly different from those of CIMP-low or CIMP-0 tumors (i.e., higher frequencies of BRAF, POLD1, MSH3, and SMAD4 mutations but lower frequencies of APC, TP53, and KRAS mutations). Multivariate analysis demonstrated that tumor, node, metastasis (TNM) stage was the independent prognostic factor affecting overall survival (OS). Among the MSI-high cases, the CIMP status did not impact the outcome of patients with MSI-high tumors. Conclusions: Only TNM stage was a statistically significant predictor of outcomes independent of CIMP profiles in MSI-high CRC patients. Sporadic MSI-high CRCs with different mechanisms of carcinogenesis have specific mutation profiles and clinicopathological features.

Highlights

10–15% of colorectal cancers (CRCs) have a high frequency of microsatellite instability (MSI) [1,2,3]
MSI-high CRCs were associated with aberrant DNA methylation; second, the molecular and clinicopathologic features of C-phosphate-G-3’ island methylator phenotype (CIMP)-high CRCs were specific to sporadic MSI-high CRCs; third, the molecular and clinicopathological features of sporadic MSI tumors with and without mismatch repair (MMR)
The Weisenberger panel consists of five markers, all of which are included in the eight markers of the Ogino panel, and the rate of CIMP-high in sporadic MSI-H CRC was 57.1% (12/21)

Summary

Introduction

10–15% of colorectal cancers (CRCs) have a high frequency of microsatellite instability (MSI) [1,2,3]. A deficiency in MMR genes results in the inefficient correction of errors in repetitive sequences (microsatellite DNA) during. Germline mutations in a DNA MMR gene are observed in ninety percent of CRC patients with. The 5’-C-phosphate-G-3’ island methylator phenotype (CIMP) is a specific phenotype of colorectal cancer (CRC) associated with microsatellite instability-high (MSI-high) tumors. Methods: In this study, we determined the CIMP status using eight methylation markers in 92 MSI-high CRC patients after excluding five germline mismatch repair (MMR) gene mutations analyzed by next-generation sequencing (NGS) and confirmed by Sanger sequencing. CIMP-high tumors showed proximal colon preponderance and female predominance.

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