Mismatch Repair (MMR) Protein Immunohistochemistry Only, Tumor
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant inherited cancer syndrome that predisposes individuals to the development of colorectal, endometrial, gastric, upper urinary tract, and other cancers. Individuals with HNPCC/Lynch syndrome have a germline mutation in 1 of several genes involved in DNA mismatch repair. The majority of mutations associated with HNPCC/Lynch syndrome occur in MSH2 and MLH1; however mutations in MSH6 and PMS2 have also been identified.
There are several strategies for evaluating individuals whose personal and/or family history of cancer is suggestive of HNPCC/Lynch syndrome. Typically, the first step is to evaluate tumors for the characteristics common to individuals with HNPCC/Lynch syndrome which include microsatellite instability (presence of numerous alterations in a type of repetitive DNA called microsatellites) and loss of protein expression of 1 or more of the genes associated with HNPCC/Lynch syndrome.
Microsatellite instability (MSI) and immunohistochemistry (IHC) are commonly interpreted together to evaluate risk for HNPCC/Lynch syndrome. High levels of MSI within a tumor are suggestive of defective DNA mismatch repair, however this finding does not provide information about which gene is involved. IHC is a complementary testing strategy used to evaluate the expression of the MLH1, MSH2, MSH6, and PMS2 proteins in HNPCC/Lynch syndrome related cancers. Loss of expression of 1 or more of these proteins 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).
IHC alone can determine retention or loss of MLH1, MSH2, MSH6, and PMS2 protein expression. If all 4 proteins are present, the likelihood of HNPCC/Lynch syndrome is reduced but not eliminated because approximately 5% of tumors that display MSI also have normal protein expression for these 4 genes. Loss of 1 or more proteins by IHC is suggestive of defective DNA mismatch repair within the tumor and the likelihood of HNPCC/Lynch syndrome is increased. Germline testing (ie, mutation analysis) for the corresponding gene(s) can then be performed to identify the causative germline mutation and allow for predictive testing of at risk individuals.
Of note, loss of protein expression by IHC has 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 are observed, MLBRF/87931 MLH1 Hypermethylation and BRAF Mutation Analyses or MLH1H/87978 MLH1 Hypermethylation Analysis, Tumor may also help to distinguish between a sporadic and germline etiology.
It should be noted that this is not a genetic test, but rather stratifies the risk of having an inherited cancer predisposition syndrome, and identifies patients who might benefit from subsequent genetic testing. See Hereditary Nonpolyposis Colorectal Cancer Testing Algorithm in Special Instructions for additional information.
Evaluation of tumor tissue to identify patients at risk for having hereditary nonpolyposis colon cancer/Lynch syndrome
Note: Mayo's preferred screening test, HNPCC/17073 Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Screen, includes both microsatellite instability and immunohistochemistry testing.
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The finding of absent protein expression for 1 or more of the MMR genes tested does not distinguish between somatic and germline mutations.
Because immunohistochemistry (IHC) results may indicate likelihood of a germline alteration, it is recommended that genetic counseling be provided prior to IHC testing.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors may occur in our interpretation of results 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. 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