Research Papers:

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway

Jung Ho Kim _, Jeong Mo Bae, Nam-Yun Cho and Gyeong Hoon Kang

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Oncotarget. 2016; 7:14095-14111. https://doi.org/10.18632/oncotarget.7374

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Jung Ho Kim1,*, Jeong Mo Bae1,*, Nam-Yun Cho2 and Gyeong Hoon Kang1,2

1 Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

2 Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

* These authors have contributed equally to this work

Correspondence to:

Gyeong Hoon Kang, email:

Keywords: colorectal cancer, CpG island methylator phenotype, microsatellite instability, MLH1, serrated pathway

Received: October 01, 2015 Accepted: January 29, 2016 Published: February 13, 2016


The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma (CRC) with the CpG island methylator phenotype (CIMP). Here, we investigated the differential characteristics of CIMP-high (CIMP-H) CRCs according to MLH1 methylation status. To further confirm the MLH1-dependent features in CIMP-H CRC, an independent analysis was performed using data from The Cancer Genome Atlas (TCGA). In our CIMP-H CRC samples, MLH1-methylated tumors were characterized by older patient age, proximal colonic location, mucinous histology, intense lymphoid reactions, RUNX3/SOCS1 promoter methylation, BRAF mutations, and microsatellite instability-high (MSI-H) status. By contrast, MLH1-unmethylated tumors were associated with earlier age of onset, increased distal colorectal localization, adverse pathologic features, and KRAS mutations. In the TCGA dataset, the MLH1-silenced CIMP-H CRC demonstrated proximal location, MSI-H status, hypermutated phenotype, and frequent BRAF mutations, but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations. In conclusion, the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status. Based on the current knowledge, the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs, whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps.

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