Interpretive Handbook

Test 88566 :
Microsatellite Instability (MSI), Tumor

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3-prime end of the EPCAM gene has also been associated with HNPCC/Lynch syndrome, as this leads to inactivation of the MSH2 promoter.


Lynch syndrome is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer associated MLH1 and MSH2 mutations (approximately 50%-80%) is generally higher than the risks associated with mutations in the other Lynch syndrome related genes and the lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are <15%. Of the 4 mismatch repair genes, mutations within the PMS2 gene confer the lowest risk for any of the tumors within the Lynch syndrome spectrum.


Several clinical variants of Lynch syndrome have been defined. These include Turcot syndrome, Muir-Torre syndrome, and homozygous mismatch repair mutations (also called constitutional mismatch repair deficiency syndrome). Turcot syndrome and Muir-Torre syndrome are associated with increased risks for cancers within the tumor spectrum described but also include brain/central nervous system malignancies and sebaceous carcinomas, respectively. Homozygous mismatch repair mutations, characterized by the presence of bi-allelic deleterious mutations within a mismatch repair gene, are associated with a different clinical phenotype defined by hematologic and brain cancers, cafe au lait macules, and childhood colon or small bowel cancer.


There are several strategies for evaluating individuals whose personal and/or family history of cancer is suggestive of HNPCC/Lynch syndrome. Tumors from individuals with HNPCC/Lynch syndrome demonstrate microsatellite instability (MSI), characterized by numerous alterations in a type of repetitive DNA called microsatellites. Two distinct MSI tumor phenotypes have been described: MSI-H (instability in >30% of microsatellites examined) and MSS/MSI-L (instability in <30% of microsatellites examined). The MSI-H phenotype is associated with germline defects in the MLH1, MSH2, MSH6, or PMS2 genes, and is the primary phenotype observed in tumors from patients with HNPCC/Lynch syndrome. Immunohistochemistry (IHC) is a complementary testing strategy to MSI testing. Most MSI-H tumors show a loss of protein expression for at least 1 of the 4 mismatch repair genes described above. Loss of expression of protein(s) within the tumor is helpful in identifying which corresponding gene(s) to target for mutation analysis. Although MSI and IHC are best interpreted together, they are also available separately to accommodate clinical situations in which there are barriers to performing these tests concurrently (eg, financial concerns, specimen requirements).


Testing is typically first performed on the tumor of an affected individual and in the context of other risk factors, such as young age at diagnosis or a strong family history of colon cancer or other HNPCC/Lynch syndrome-related cancers. If defective DNA mismatch repair is identified within the tumor, mutation analysis of the associated gene can be performed to identify the causative germline mutation and allow for predictive testing of at risk individuals.


Of note, MSI-H phenotypes and loss of protein expression by IHC have also been demonstrated in various sporadic cancers, including those of the colon and endometrium. Absence of MLH1 and PMS2 protein expression within a tumor, for instance, is most often associated with a somatic alteration in individuals with an older age of onset of cancer than typical HNPCC/Lynch syndrome families. Therefore, an MSI-H phenotype or loss of protein expression by IHC within a tumor does not distinguish between somatic and germline mutations. Genetic testing of the gene indicated by IHC analysis can help to distinguish between these 2 possibilities. In addition, when absence of MLH1/PMS2 is observed, MLBRF / MLH1 Hypermethylation and BRAF Mutation Analyses, Tumor or MLH1H / MLH1 Hypermethylation Analysis, Tumor may also help to distinguish between a sporadic and germline etiology.


It should be noted that MSI testing is not a genetic test, but rather helps to stratify the risk of having an inherited cancer predisposition syndrome, and identifies patients who might benefit from subsequent genetic testing. Immunohistochemistry is available as an add-on to this test (IHCO / Mismatch Repair (MMR) Protein Immunohistochemistry Only, Tumor). If both MSI and IHC are desired, please order the profile test, HNPCC screen (HNPCC / Hereditary Nonpolyposis Colorectal Cancer [HNPCC] Screen). See Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm in Special Instructions for additional information.


Evaluation for MSI may also be valuable for clinical decision making. Colon cancers that demonstrate defective DNA mismatch repair (MSI-H) have a significantly better prognosis compared to those with intact mismatch repair (MSS/MSI-L). Additionally, current data indicate that stage II and stage III patients with colon cancers characterized by the presence of defective MMR (MSI-H) may not benefit from treatment with fluorouracil (5-FU) alone or in combination with leucovorin (LV). These findings are most likely to impact the management of patients with stage II disease.

Useful For Suggests clinical disorders or settings where the test may be helpful

Evaluation of tumor tissue to identify patients at high risk for having hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome


Note: Mayo's preferred screening test (HNPCC / Hereditary Nonpolyposis Colorectal Cancer [HNPCC] Screen) includes both microsatellite instability (MSI) and Immunohistochemistry (IHC) testing.


Evaluation of tumor tissue for clinical decision making purposes given the prognostic implications associated with MSI phenotypes

Interpretation Provides information to assist in interpretation of the test results

The report will include specimen information, assay information, and interpretation of test results. Microsatellite stable (MSS) is reported as MSS/MSI-L (0 or 1 of 5 markers demonstrating instability) or MSI-H (2 or more of 5 markers demonstrating instability).

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

The finding of tumor microsatellite instability does not distinguish between somatic and germline mutations.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given to us is inaccurate or incomplete.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Baudhuin LM, Burgart LJ, Lentovich O, Thibodeau SN: Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch Syndrome. Fam Cancer 2005;4(3):255-265

2. Terdiman JP, Gum JR Jr, Conrad PG, et al: Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 2001 January;120(1):21-30

3. Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. JCO 2005 23(3):609-618

4. 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 349:247-57

5. Lynch Syndrome–GeneReviews–NCBI Bookshelf. Available from URL: