Screening for Microsatellite Instability in Colorectal Cancer and Lynch Syndrome - A Mini Review

Minhua Wang, Kazunori Kanehira, Frank Chen


Colorectal cancers with high frequency microsatellite instability (MSI-H) account for 15-20% of all colorectal cancers (CRC).  The familial form of MSI-H CRC is Lynch syndrome, caused by germline mutation in mismatch repair (MMR) genes, accounting for 3-5% of all CRC.  Universal screening in newly diagnosed colorectal cancers is recommended by many experts.  MSI status is a marker of prognosis and a predictive factor of response to chemotherapy and immunotherapy.  MSI DNA testing and immunohistochemical study for MMR proteins are commonly used screening tools, both with high sensitivity and specificity.  IHC is an easily accessible and cost effective approach with the advantage over MSI testing of being able to pinpoint the mutated gene.  It is widely used as an initial primary test for detection of MSI-H tumors.


colorectal cancer, microsatellite instability, MSI, Lynch Syndrome, MLH1, MSH2, MSH6, PMS2

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Centers for disease control and prevention (CDC). Colorectal Cancer Statistics. Accessed 01/14, 2016.

Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073-2087.

Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851-1860.

Salovaara R, Loukola A, Kristo P, et al. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2000;18:2193-2200.

de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 2010;28:3380-3387.

Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: IARC; 2010.

Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology. 1993;104:1535-1549.

College of American Pathologists (CAP). Prognostic Uses of MSI Testing. May, 2011; Accessed on 1/14/2016.

Hall G, Clarkson A, Shi A, et al. Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. Pathology. 2010;42:409-413.

Buchanan DD, Roberts A, Walsh MD, Parry S, Young JP. Lessons from Lynch syndrome: a tumor biology-based approach to familial colorectal cancer. Future Oncol. 2010;6:539-549.

Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011;42:1-10.

Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994;368:258-261.

Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994;263:1625-1629.

Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993;75:1215-1225.

Akiyama Y, Sato H, Yamada T, et al. Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res. 1997;57:3920-3923.

Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17:271-272.

Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology. 2006;130:312-322.

Nicolaides NC, Papadopoulos N, Liu B, et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994;371:75-80.

Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat. 2009;30:197-203.

Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. 2009;41:112-117.

Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919-932.

Wagner A, Barrows A, Wijnen JT, et al. Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet. 2003;72:1088-1100.

Casey G, Lindor NM, Papadopoulos N, et al. Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. JAMA. 2005;293:799-809.

Gill S, Lindor NM, Burgart LJ, et al. Isolated loss of PMS2 expression in colorectal cancers: frequency, patient age, and familial aggregation. Clin Cancer Res. 2005;11:6466-6471.

Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304-2310.

Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81:214-218.

Bansidhar BJ. Extracolonic manifestations of lynch syndrome. Clin Colon Rectal Surg.25:103-110.

Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609-618.

Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247-257.

Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan B. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890-1896.

Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372:2509-2520.

Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991;34:424-425.

Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116:1453-1456.

Pinol V, Castells A, Andreu M, et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005;293:1986-1994.

Raedle J, Trojan J, Brieger A, et al. Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer. Ann Intern Med. 2001;135:566-576.

Wullenweber HP, Sutter C, Autschbach F, et al. Evaluation of Bethesda guidelines in relation to microsatellite instability. Dis Colon Rectum. 2001;44:1281-1289.

Jenkins MA, Hayashi S, O'Shea AM, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology. 2007;133:48-56.

Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011;135:1269-1277.

Jass JR. HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Fam Cancer. 2004;3:93-100.

Kievit W, de Bruin JH, Adang EM, et al. Current clinical selection strategies for identification of hereditary non-polyposis colorectal cancer families are inadequate: a meta-analysis. Clin Genet. 2004;65:308-316.

Group EoGAiPaPEW. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009;11:35-41.

Hampel H. Point: justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer. J Natl Compr Canc Netw. 2010;8:597-601.

National Comprehensive Cancer Network (NCCN), Clinical Practice Guidelines in Oncology™ v. 2. 2013; Accessed 01/14, 2016.

Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248-5257.

Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58:1713-1718.

Verma L, Kane MF, Brassett C, et al. Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. J Med Genet. 1999;36:678-682.

Wu Y, Berends MJ, Mensink RG, et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999;65:1291-1298.

Suraweera N, Duval A, Reperant M, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002;123:1804-1811.

Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-268.

Cicek MS, Lindor NM, Gallinger S, et al. Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry. J Mol Diagn. 2011;13:271-281.

You JF, Buhard O, Ligtenberg MJ, et al. Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats. Br J Cancer.103:1840-1845.

Harfe BD, Minesinger BK, Jinks-Robertson S. Discrete in vivo roles for the MutL homologs Mlh2p and Mlh3p in the removal of frameshift intermediates in budding yeast. Curr Biol. 2000;10:145-148.

Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell. 2006;126:297-308.

Acharya S, Wilson T, Gradia S, et al. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci U S A. 1996;93:13629-13634.

Young J, Simms LA, Biden KG, et al. Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol. 2001;159:2107-2116.

Boland CR, Koi M, Chang DK, Carethers JM. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Fam Cancer. 2008;7:41-52.

Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol. 2011;5:385-399.

South CD, Yearsley M, Martin E, Arnold M, Frankel W, Hampel H. Immunohistochemistry staining for the mismatch repair proteins in the clinical care of patients with colorectal cancer. Genet Med. 2009;11:812-817.

Kim JH, Kang GH. Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. World J Gastroenterol. 2014;20:4230-4243.

Watson N, Grieu F, Morris M, et al. Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer. J Mol Diagn. 2007;9:472-478.

Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn. 2008;10:293-300.

Shia J, Klimstra DS, Nafa K, et al. Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol. 2005;29:96-104.

Shia J, Ellis NA, Klimstra DS. The utility of immunohistochemical detection of DNA mismatch repair gene proteins. Virchows Arch. 2004;445:431-441.

Petras RE. Gastrointestinal Pathology: New Approaches to Old Problems Pathology Today. American Society for Clinical Pathology Annual Meeting Las Vegas, Nevada 2011.

Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006;354:2751-2763.


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