MSI and IHC testing
Quick facts: Microsatellite instability
and immunohistochemistry testing
for Lynch syndrome/hereditary nonpolyposis colorectal cancer
Purpose
Microsatellite instability (MSI) and/or immunohistochemistry (IHC) testing is performed to analyze colon
and other tumor tissue samples for features suggestive of Lynch syndrome/hereditary non-polyposis
colorectal cancer (HNPCC). The tests aid in targeting gene sequencing of the mismatch repair genes
(MLH1, MSH2, PMS2 and MSH6) and screen out individuals who are unlikely to have Lynch syndrome.
MSI and/or IHC testing are often the first steps for individuals suspected to have Lynch/HNPCC (see
“Revised Bethesda guidelines”). MSI and IHC testing is complex; consider consulting with a genetics
professional for guidance.
What MSI and IHC testing identify
Tumors from individuals with mutations in the mismatch repair genes have two distinguishing
characteristics:
• Microsatellite instability, which is the expansion or reduction in the length of repetitive DNA
sequences (known as microsatellites) in the tumor DNA compared to normal DNA
• Loss of one or two of the mismatch repair proteins in the tumor as compared to normal tissue
MSI testing can detect an abnormal number of microsatellite repeats, which indicates that the cancer
more likely arose from cells with defective mismatch repair genes. A result of “MSI-high” means that a
high number of microsatellite repeats were found.
IHC testing can detect the presence or absence of the protein products of the mismatch repair genes. A
missing protein suggests a mutation in the gene that codes for that protein.
MSI/IHC sensitivity and specificity
Sensitivity: Likelihood that the test will be positive (test will detect the mutation) if mutation is present.
Specificity: Likelihood that the test will be negative (test will not detect the mutation) when mutation is
not present.
MSI testing:
• Has 80–91 percent sensitivity among those with MLH1 or MSH2 mutations; depending on
composition of MSI panel, specificity may be as high as 90 percent
• Has 55–77 percent sensitivity among those with MSH6 or PMS2 mutations; depending on
composition of MSI panel, specificity may be as high as 90 percent
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MSI and IHC testing
IHC testing:
• Has 83 percent sensitivity regardless of MMR gene involved; specificity is 89 percent
Source: EGAPP, 2009
When to Order MSI/IHC
Source
Recommendation
NCCN recommendations for MSI testing
of colorectal tumors based on “Revised
Bethesda Criteria”
Order MSI testing for the following
indications:
• CRC diagnosed in a patient who is less than
50 years old
• Presence of synchronous, metachronous
colorectal or HNPCC-associated tumors†,
regardless of age
• CRC with MSI-high histology‡ in a patient
< age 60
• CRC diagnosed in a patient with one or
more FDRs* with an HNPCC-related cancer
when one of the cancers was diagnosed
prior to age 50
• CRC diagnosed in a patient with two or
more FDRs* or SDRs** with an HNPCCrelated cancer, regardless of age
EGAPP recommendations for MSI/IHC testing
of colorectal tumors of individuals with
newly-diagnosed CRC
• MSI or IHC testing for all newly-diagnosed
patients with colorectal cancer, with followup genetic testing as warranted
* FDRs= first-degree relatives, i.e., parents, siblings, children
** SDRs= second-degree relatives, i.e., grandparents, uncles/aunts, nieces and nephews
HNPCC-related tumors include colorectal, endometrial, gastric, ovarian, pancreatic, ureter/renal pelvis, biliary
tract and brain (usually glioblastoma as seen in Turcot syndrome) tumors, sebaceous gland adenomas and
keratoacanthomas in Muir–Torre syndrome and carcinoma of the small bowel.
†
‡
resence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation
P
or medullary growth pattern.
MSI testing is preferably performed on colon cancer tissue but can be done on adenomatous
polyps or endometrial or ovarian cancer tumors. IHC testing is preferably done on colon tumor
tissue.
See genetests.org for laboratories that perform the testing.
Basic concepts in the interpretation of MSI and IHC
• MSI testing will identify tumors that have microsatellite instability (i.e., MSI-high tumors)
• IHC testing will detect the presence or absence of the protein products of the mismatch
repair genes (MLH1, MSH2, PMS2 and MSH6)
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MSI and IHC Xxxxxx
testing
• The odds of having Lynch syndrome in a patient with CRC are approximately one in five if
the patient’s tumor is found to be MSI-high or to have abnormal IHC
As a result, MSI and IHC are effective tools to screen for colorectal cancer patients
who are more likely to have Lynch syndrome.
When interpreting MSI or IHC results, also consider that:
• Approximately 3 percent of all CRC cases are caused by Lynch syndrome
• About 13 percent of all colorectal tumors are MSI-high
• Approximately 25 percent of all colorectal tumors have abnormal IHC
Thus, MSI and IHC testing are not diagnostic because many patients with MSI-high
tumors or tumors with abnormal IHC do not have Lynch syndrome.
For more information about interpretation and follow up, see the “Overview of testing for Lynch
syndrome tool”.
Related content:
Revised Bethesda guidelines
Overview of testing for Lynch syndrome
References:
NCCN Clinical Practice Guidelines in Oncology (2011). Colorectal Cancer Screening V.2.2011 Accessed December 17,
2010 from www.nccn.org/professionals/physician_gls/f_guidelines.asp
MSI testing guidelines in section LS-A, based on Bethesda guidelines
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009). 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 relatives, Genetics in Medicine, 11(1), 35-41.
Hendriks, Y. M., de Jong, A. E., Morreau, H., Tops, C. M., Vasen, H. F., Wijnen, J. T., et al. (2006). Diagnostic approach and
management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA: A Cancer
Journal for Clinicians, 56(4), 213-225.
Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., de la Chapelle, A., Ruschoff, J., et al. (2004). Revised Bethesda Guidelines
for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst, 96(4),
261–268.
11-0456:2/12:jt:Updated Feb 2012
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