Gastric cancer (stomach cancer) is characterized by significant molecular diversity, meaning tumors do not all behave or respond to treatment the same way. Identifying specific molecular subtypes allows for personalized treatment plans. The molecular profile known as Microsatellite Instability-High (MSI-High or MSI-H) defines an important subgroup of gastric tumors. This classification identifies a cancer type with unique biological features that influence both the choice of therapy and the patient’s long-term outlook.
Understanding Microsatellite Instability
Microsatellites are short, repetitive stretches of DNA sequences found throughout the human genome. These sequences are susceptible to errors when the cell divides and replicates its DNA. Normally, the Mismatch Repair (MMR) system corrects these replication errors, ensuring the microsatellite sequences remain stable.
In a subset of gastric cancers, the MMR system becomes defective or non-functional, failing to correct these replication mistakes. The MMR system relies on proteins, including MLH1, MSH2, MSH6, and PMS2, to function. When the genes coding for these proteins are inactivated, the repair mechanism fails, and errors accumulate rapidly.
This failure results in a hypermutated state where the microsatellite sequences become variable and unstable, defined as microsatellite instability. MSI-High tumors show instability in many markers, leading to a high number of mutations. This biological behavior differs significantly from tumors where the MMR system is functional, which are classified as Microsatellite Stable (MSS).
Identifying MSI Status in Gastric Cancer
Determining the MSI status of a gastric tumor is standard practice upon initial diagnosis because of its direct impact on treatment decisions. Testing is performed on tissue samples obtained during a biopsy or surgical removal. The goal is to determine if the tumor has a functional MMR system or if it is deficient (dMMR), which correlates with the MSI-H phenotype.
Two primary methods assess this status.
Immunohistochemistry (IHC)
IHC uses specialized stains to visualize the presence or absence of the four main MMR proteins within the tumor cells’ nuclei. The absence of one or more of these proteins indicates a deficient MMR system, classifying the tumor as dMMR. The four proteins are:
- MLH1
- MSH2
- MSH6
- PMS2
DNA Sequence Analysis
The second method involves directly analyzing the DNA sequences, often through Polymerase Chain Reaction (PCR) or Next-Generation Sequencing (NGS). These techniques compare the length of specific microsatellite markers in the tumor DNA to the length in normal DNA. If a high proportion of markers show length variations, the tumor is classified as MSI-High. While IHC is an effective initial screening tool, molecular methods provide direct confirmation.
Treatment Implications of MSI-High Status
The identification of MSI-H status is a predictive biomarker that fundamentally shifts the treatment approach. This molecular profile is strongly associated with a response to immune checkpoint inhibitors, a form of immunotherapy. The high mutation burden characteristic of MSI-H tumors is the biological reason for this increased responsiveness.
As the MMR system fails, the tumor accumulates thousands of somatic mutations, resulting in abnormal proteins called neoantigens. These neoantigens are foreign to the immune system, making the tumor recognizable and “hot” in terms of immune activity. Immune checkpoint inhibitors, such as anti-PD-1 agents, work by releasing the brakes on the immune system, allowing activated T-cells to target and destroy the cancer cells.
The clinical success of immunotherapy in this subgroup has been transformative, leading to the approval of these agents for MSI-H solid tumors, including gastric cancer. Studies show significantly higher objective response rates—often exceeding 40% in advanced disease—with immunotherapy compared to traditional chemotherapy. MSI-H tumors generally show a poor response to conventional chemotherapy compared to their MSS counterparts.
In the advanced, metastatic setting, immunotherapy is typically the preferred first-line treatment. For patients with localized but advanced disease, immunotherapy is increasingly used in the neoadjuvant setting (before surgery), often leading to deep pathological responses. This strategy contrasts sharply with the treatment of MSS tumors, where chemotherapy remains the backbone of initial therapy.
Prognosis and Clinical Outlook
The MSI-H subtype of gastric cancer carries a distinct and generally more favorable long-term outlook compared to Microsatellite Stable tumors. Even before modern immunotherapy, MSI-H tumors were associated with improved overall survival rates. This biological advantage is attributed to the fact that these hypermutated tumors naturally provoke a strong immune response, often showing a dense infiltration of immune cells.
Patients diagnosed with MSI-H gastric cancer tend to present with specific clinicopathological features. These include older age, female predominance, and tumors located in the distal part of the stomach. Furthermore, this subtype is often diagnosed at an earlier stage and is associated with a reduced risk of lymph node metastasis and invasion into surrounding tissues. This less aggressive natural history contributes to the better prognosis observed.
The superior survival rates observed in MSI-H patients are significantly bolstered by the efficacy of immune checkpoint inhibitors. The durable responses seen with immunotherapy reinforce the positive clinical outlook for patients identified with this specific molecular signature. The MSI-H biomarker serves as an indicator of both therapeutic sensitivity and long-term prognosis.