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Genes 2015, 6(2), 185-205; doi:10.3390/genes6020185

EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression

Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
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Author to whom correspondence should be addressed.
Academic Editor: Maija Kohonen-Corish
Received: 24 February 2015 / Revised: 19 March 2015 / Accepted: 23 March 2015 / Published: 31 March 2015
(This article belongs to the Special Issue Microsatellite Instability)
View Full-Text   |   Download PDF [516 KB, uploaded 31 March 2015]   |  

Abstract

DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3. View Full-Text
Keywords: DNA mismatch repair; microsatellite instability; genomic instability; colorectal cancer; MSH3; MutSβ; inflammation; short tandem repeats; EMAST; patient survival; patient outcome DNA mismatch repair; microsatellite instability; genomic instability; colorectal cancer; MSH3; MutSβ; inflammation; short tandem repeats; EMAST; patient survival; patient outcome
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Carethers, J.M.; Koi, M.; Tseng-Rogenski, S.S. EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression. Genes 2015, 6, 185-205.

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