title: EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression.
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.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. jcarethe@umich.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Carethers
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. mkoi@med.umich.edu.
authors.forename: Minoru
authors.initials: M
authors.lastname: Koi
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. sstseng@med.umich.edu.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Tseng-Rogenski
references.citation: Clin Cancer Res. 2008 Sep 1;14 (17 ):5476-83
references.pmid: 18765539
references.citation: Biochem Biophys Res Commun. 1996 Oct 14;227(2):553-7
references.pmid: 8878551
references.citation: Ann Oncol. 2015 Jan;26(1):126-32
references.pmid: 25361982
references.citation: Cell Res. 2013 Apr;23(4):565-72
references.pmid: 23337586
references.citation: Biochim Biophys Acta. 2012 Apr;1823(4):889-99
references.pmid: 22343000
references.citation: PLoS One. 2012;7(11):e50616
references.pmid: 23226332
references.citation: Nat Rev Clin Oncol. 2012 Oct;9(10):561-70
references.pmid: 22910681
references.citation: Cancer Res. 2001 Feb 15;61(4):1619-23
references.pmid: 11245474
references.citation: PLoS One. 2014 Jun 23;9(6):e100461
references.pmid: 24956473
references.citation: Gene. 2001 Jul 11;272(1-2):301-13
references.pmid: 11470537
references.citation: Hum Mol Genet. 2010 Jul 1;19(13):2638-47
references.pmid: 20418486
references.citation: Curr Colorectal Cancer Rep. 2010 Jan;6(1):24-29
references.pmid: 20157368
references.citation: Gastroenterology. 2008 Oct;135(4):1079-99
references.pmid: 18773902
references.citation: Oncogene. 2008 Jul 10;27(30):4200-9
references.pmid: 18345027
references.citation: Dig Dis Sci. 2015 Mar;60(3):711-21
references.pmid: 25540085
references.citation: Cancer Res. 1998 Nov 15;58(22):5248-57
references.pmid: 9823339
references.citation: J Mol Med (Berl). 2006 Apr;84(4):329-33
references.pmid: 16416315
references.citation: Mutat Res. 2013 Mar-Apr;743-744:67-77
references.pmid: 23206442
references.citation: PLoS One. 2013 May 28;8(5):e65369
references.pmid: 23724141
references.citation: J Gastrointest Surg. 2010 Oct;14(10):1521-8
references.pmid: 20844976
references.citation: J Biol Chem. 2011 Apr 8;286(14 ):12157-65
references.pmid: 21285347
references.citation: Nature. 2012 Jul 18;487(7407):330-7
references.pmid: 22810696
references.citation: Mutat Res. 2012 Jan 3;729(1-2):73-80
references.pmid: 22001236
references.citation: Science. 1993 May 7;260(5109):812-6
references.pmid: 8484121
references.citation: Dig Dis Sci. 2012 Jan;57(1):72-8
references.pmid: 21773681
references.citation: Cancer Res. 2008 Oct 15;68(20):8465-72
references.pmid: 18922920
references.citation: Fam Cancer. 2008;7(1):41-52
references.pmid: 17636426
references.citation: Gastroenterology. 2014 Mar;146(3):602-4
references.pmid: 24468183
references.citation: DNA Repair (Amst). 2013 Jan 1;12(1):46-52
references.pmid: 23228367
references.citation: Am J Physiol Cell Physiol. 2002 Jul;283(1):C148-54
references.pmid: 12055083
references.citation: Cancer Res. 2001 Oct 15;61(20):7603-7
references.pmid: 11606400
references.citation: Cancer Discov. 2014 May;4(5):592-605
references.pmid: 24556366
references.citation: Int J Cancer. 2002 Sep 1;101(1):23-31
references.pmid: 12209584
references.citation: PLoS One. 2012;7(11):e50541
references.pmid: 23209772
references.citation: Mol Cell. 2005 Mar 18;17(6):793-803
references.pmid: 15780936
references.citation: Gastroenterology. 2015 Mar;148(3):579-89
references.pmid: 25461668
references.citation: Br J Cancer. 2000 Feb;82(4):913-23
references.pmid: 10732766
references.citation: Science. 1993 May 7;260(5109):816-9
references.pmid: 8484122
references.citation: Cancer Res. 1998 Feb 15;58(4):594-8
references.pmid: 9485005
references.citation: Stem Cells. 2008 Aug;26(8):2052-62
references.pmid: 18511603
references.citation: Oncogene. 2002 Jul 25;21(32):4894-9
references.pmid: 12118368
references.citation: Nature. 1993 Jun 10;363(6429):558-61
references.pmid: 8505985
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):E837-44
references.pmid: 21960445
references.citation: Br J Cancer. 2008 Nov 18;99(10 ):1607-12
references.pmid: 18941461
references.citation: Cancer Res. 2000 May 1;60(9):2488-91
references.pmid: 10811129
references.citation: Oncol Rep. 2010 Feb;23(2):551-61
references.pmid: 20043121
references.citation: Oncogene. 2014 Jul 24;33(30):3939-46
references.pmid: 24013230
references.citation: Cancer Res. 1996 Mar 15;56(6):1237-40
references.pmid: 8640805
references.citation: J Cell Biochem. 2011 Jun;112(6):1612-21
references.pmid: 21344488
references.citation: Gastroenterology. 2004 Feb;126(2):394-401
references.pmid: 14762775
references.citation: Science. 1996 Feb 2;271(5249):659-62
references.pmid: 8571131
references.citation: Cancer Res. 1999 Oct 15;59(20):5068-74
references.pmid: 10537275
references.citation: Cancer Res. 2000 Apr 15;60(8):2225-31
references.pmid: 10786688
references.citation: Gastroenterology. 2012 Jul;143(1):48-50.e1
references.pmid: 22465427
references.citation: Int J Biol Sci. 2013 Dec 19;10(1):73-9
references.pmid: 24391453
references.citation: Cancer Res. 1995 Oct 1;55(19):4264-7
references.pmid: 7671233
references.citation: Oncogene. 2010 Apr 15;29(15):2172-80
references.pmid: 20140012
references.citation: J Clin Oncol. 2009 Apr 10;27(11):1814-21
references.pmid: 19273709
references.citation: Gut. 2012 Jun;61(6):847-54
references.pmid: 22427238
references.citation: Br J Cancer. 2014 Aug 26;111(5):823-7
references.pmid: 24691426
references.citation: Gastroenterology. 2011 Aug;141(2):411-2
references.pmid: 21708155
references.citation: Cancer. 2011 Feb 1;117(3):492-500
references.pmid: 20845481
references.citation: Cell Rep. 2014 Jul 24;8(2):501-13
references.pmid: 25043185
references.citation: Gastroenterology. 2010 Jun;138(6):2073-2087.e3
references.pmid: 20420947
references.citation: PLoS Genet. 2013;9(2):e1003280
references.pmid: 23468640
references.citation: Int J Cancer. 2000 May 20;89(3):230-5
references.pmid: 10861498
references.citation: PLoS One. 2011;6(12 ):e28117
references.pmid: 22164234
references.citation: Mutat Res. 2013 Jul-Aug;747-748:19-27
references.pmid: 23643670
references.citation: Genes Chromosomes Cancer. 2000 Sep;29(1):33-9
references.pmid: 10918391
references.citation: Cancer Res. 2009 Aug 15;69(16):6423-9
references.pmid: 19638594
references.citation: Cancer Lett. 2003 Jun 10;195(2):243-51
references.pmid: 12767533
references.citation: Int J Oncol. 2013 May;42(5):1644-53
references.pmid: 23546019
references.citation: Ann Oncol. 2014 May;25(5):1032-8
references.pmid: 24585723
references.citation: J Biol Chem. 2000 Jun 16;275(24):18424-31
references.pmid: 10747992
references.citation: Gastroenterology. 2010 Nov;139(5):1519-25
references.pmid: 20708618
references.citation: Cancer Res. 2003 Sep 15;63(18):5738-44
references.pmid: 14522894
references.citation: J Cell Mol Med. 2013 Sep;17(9):1088-95
references.pmid: 24151976
references.citation: Mol Cell Biol. 2003 May;23 (9):3265-73
references.pmid: 12697826
references.citation: J Clin Oncol. 2005 Jan 20;23(3):609-18
references.pmid: 15659508
references.citation: Cancer Sci. 2011 Sep;102(9):1706-11
references.pmid: 21679278