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World J Gastroenterol. Apr 21, 2014; 20(15): 4230-4243
Published online Apr 21, 2014. doi: 10.3748/wjg.v20.i15.4230
Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer
Jung Ho Kim, Gyeong Hoon Kang
Jung Ho Kim, Department of Pathology, SMG-SNU Boramae Medical Center, Seoul 156-707, South Korea
Gyeong Hoon Kang, Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, South Korea
Gyeong Hoon Kang, Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea
Author contributions: Kim JH performed the literature review and drafted the article; Kang GH revised and edited the article; all of the authors have read and approved the final version of the article.
Supported by The National R&D Program for Cancer Control funded by the Ministry of Health and Welfare, South Korea, No. 0720540; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP), No. 2011-0030768; Priority Research Centers Program through the NRF grant funded by the Ministry of Education, Science and Technology (MEST), South Korea, No. 2009-0093820; and the Mid-career Researcher Program through the NRF grant funded by MEST, No. 2011-0015646
Correspondence to: Gyeong Hoon Kang, MD, PhD, Professor, Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea. ghkang@snu.ac.kr
Telephone: +82-2-7408263 Fax: +82-2-7655600
Received: September 25, 2013
Revised: January 30, 2014
Accepted: February 20, 2014
Published online: April 21, 2014
Processing time: 204 Days and 4.4 Hours
Abstract

Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn’s-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.

Keywords: Colorectal cancer; Microsatellite instability; DNA mismatch repair; DNA methylation; CpG islands; Prognosis; Adjuvant chemotherapy

Core tip: A high level of microsatellite instability (MSI-H) is a known molecular indicator of a favorable prognosis and low benefit of 5-fluorouracil-based adjuvant chemotherapy in patients with colorectal cancer (CRC). However, MSI-H CRCs are molecularly heterogeneous tumors, which are characterized by DNA mismatch repair deficiency and various genetic and epigenetic alterations. Therefore, we hypothesized that MSI-H CRCs can be divided into prognostic subgroups based on the molecular heterogeneity. This article provides an up-to-date review concerning the underlying molecular features of MSI-H CRCs and potential prognostic or predictive molecular markers for MSI-H CRCs.