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Updated: Jun 12, 2026
Evaluation of Colorectal Cancer Risk and Prevalence by Stool DNA Integrity Detection
Published on: June 8, 2020
Clinical relevance of microsatellite instability in colorectal cancer
Albert de la Chapelle1, Heather Hampel
1Ohio State University, Comprehensive Cancer Center, Columbus, OH 43210, USA. albert.delachapelle@osumc.edu
Abstract:
Microsatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. It arises in tumors with deficient mismatch repair due to the inactivation of one of the four mismatch repair genes: MSH2, MLH1, MSH6, and PMS2. In order to determine the MSI status of a tumor, microdissection and polymerase chain reaction-based detection strategies are required. For practical purposes, MSI is equivalent to the loss of staining by immunohistochemistry (IHC) of one of the mismatch repair genes since both signify an abnormality in mismatch repair. Of all colorectal cancers (CRCs), 15% to 20% display MSI or abnormal IHC (often referred to as microsatellite instability [MIN] pathway). The remaining 80% to 85% of CRCs are microsatellite stable but most are characterized by chromosomal instability (CIN pathway). Almost all Lynch syndrome tumors have MSI or abnormal IHC and they account for up to one third of all MIN CRCs (3% to 5% of all CRCs). The remaining MIN tumors are sporadic as a result of somatic inactivation of the MLH1 gene caused by methylation of its promoter. Thus, the presence of a MSI/IHC abnormality prompts further investigations to diagnose Lynch syndrome, whereas its absence excludes Lynch syndrome. We recommend screening all CRC tumors for IHC or MSI. MIN tumors have a more favorable outcome than CIN tumors, and fluorouracil-based adjuvant chemotherapy does not improve the outcome of stage II or stage III MIN tumors. More data are needed to determine how best to treat patients with stage II and stage III MIN CRCs.
Insights
Microsatellite instability (MSI) testing is crucial for colorectal cancer (CRC) diagnosis. MSI or abnormal immunohistochemistry (IHC) in CRC tumors warrants further Lynch syndrome investigation.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Microsatellite instability (MSI) is a hallmark of deficient DNA mismatch repair, often caused by the inactivation of MSH2, MLH1, MSH6, or PMS2 genes.
- In colorectal cancer (CRC), 15-20% of tumors exhibit MSI or abnormal immunohistochemistry (IHC), termed the microsatellite instability (MIN) pathway, contrasting with the chromosomally unstable (CIN) pathway in 80-85% of CRCs.
- Lynch syndrome tumors frequently present with MSI/abnormal IHC, accounting for a significant portion of MIN CRCs, while sporadic MIN tumors often result from MLH1 promoter methylation.
Purpose of the Study:
- To highlight the significance of MSI and IHC in diagnosing colorectal cancer subtypes.
- To underscore the role of MSI/IHC testing in identifying potential Lynch syndrome cases.
- To discuss the prognostic implications and treatment considerations for MSI/MIN tumors in CRC.
Main Methods:
- Utilizing microdissection and polymerase chain reaction (PCR) for MSI status determination.
- Employing immunohistochemistry (IHC) as a practical surrogate for MSI detection by assessing mismatch repair gene protein expression.
- Analyzing the association between MSI status, tumor type (Lynch syndrome vs. sporadic), and patient outcomes.
Main Results:
- MSI or abnormal IHC in CRC indicates a deficient mismatch repair system.
- The presence of MSI/IHC abnormality necessitates further evaluation for Lynch syndrome.
- MIN tumors generally have a better prognosis than CIN tumors, but current chemotherapy regimens show limited benefit for stage II/III MIN CRCs.
Conclusions:
- Screening all CRC tumors for MSI or IHC is recommended.
- MSI/IHC testing is pivotal for differentiating between Lynch syndrome and sporadic colorectal cancers.
- Further research is required to optimize treatment strategies for stage II and III MIN colorectal cancers.
