Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jan 15, 2018; 10(1): 1-14
Published online Jan 15, 2018. doi: 10.4251/wjgo.v10.i1.1
Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer
Minoru Koi, Stephanie S Tseng-Rogenski, John M Carethers
Minoru Koi, Stephanie S Tseng-Rogenski, John M Carethers, Division of Gastroenterology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109-5368, United States
Author contributions: All three authors wrote and edited this manuscript.
Supported by United States Public Health Service, Nos. DK067287, CA162147 and CA206010; and the A. Alfred Taubman Medical Research Institute of the University of Michigan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: John M Carethers, BSc, MD, Full Professor, Professor and Chair, Division of Gastroenterology, Department of Internal Medicine, and Comprehensive Cancer Center, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5368, United States.
Telephone: +1-734-6151717 Fax: +1-734-9367024
Received: October 26, 2017
Peer-review started: October 29, 2017
First decision: November 23, 2017
Revised: November 29, 2017
Accepted: December 6, 2017
Article in press: December 6, 2017
Published online: January 15, 2018

Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair (MMR). About 15% of sporadic colorectal cancers (CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono- and di-nucleotide frameshifts to classify it as microsatellite instability-high (MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic non-MSI-H CRCs demonstrate frameshifts at di- and tetra-nucleotide microsatellites to classify it as MSI-low/elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation’s effect upon the DNA MMR system.

Keywords: Microsatellite instability, Microsatellite stable, Elevated microsatellite alterations at selected tetranucleotide repeats, Colorectal cancer, Mismatch repair, Inflammation, MSH3

Core tip: Inflammation can trigger microsatellite stable colorectal cancers (CRCs) to acquire a nuclear-to-cytoplasm displacement of the DNA mismatch repair protein MSH3, rendering the CRC with di- and tetranucleotide microsatellite instability (MSI-low/elevated microsatellite alterations at selected tetranucleotide repeats) and modifying the biological behavior of the CRC towards metastasis and poor patient survival. We herein discuss the mechanisms and significance of these induced inflammatory-associated microsatellite alterations, and suggest three content areas to further examine interventions that may modify the observed behavior of these CRCs.