A tumor classified as microsatellite stable (MSS) possesses a form of genetic stability. This classification is determined by examining specific, short, repeating sequences of DNA known as microsatellites, which are found throughout the human genome. When a tumor is designated as MSS, these repetitive DNA segments maintain a consistent, unmutated length, indicating a stable genome within the cancer cell. The MSS classification provides direction for personalized treatment strategies in various cancers.
The Basis of Stability: Microsatellites and DNA Repair
Microsatellites are short tracts of DNA where a sequence of one to six base pairs is repeated multiple times. During cell division, errors can occur when DNA is copied, especially in these highly repetitive regions. The Mismatch Repair (MMR) system acts as the cell’s genetic “proofreader” to correct these mistakes.
The MMR system is a complex of proteins that scans the newly copied DNA strand for mispaired bases or small insertion and deletion loops. When the MMR machinery detects an error, it excises the faulty section and ensures the correct sequence is inserted. An MSS tumor is stable because its MMR system is intact and proficient, successfully repairing nearly all replication errors. This ensures the microsatellite sequences in the tumor cells are the same length as those in the patient’s healthy cells.
Defining Microsatellite Stable Status
The microsatellite stable (MSS) status describes a tumor’s ability to maintain the integrity of its repetitive DNA sequences. Clinically, this means that zero or only a very small number of tested microsatellite markers show a change in length when compared to normal tissue. This status is the most common finding across many human cancers.
Determining this status is a routine clinical procedure, typically performed on tumor tissue obtained through biopsy or surgery. Two primary laboratory methods are used to assign the MSS status.
One method involves Polymerase Chain Reaction (PCR) testing, which compares the length of a standardized panel of five microsatellite markers in the tumor against the patient’s normal tissue. If none or only one marker shows a length change, the tumor is classified as MSS. The second approach is immunohistochemistry (IHC), which indirectly assesses stability by checking for the presence of the Mismatch Repair (MMR) proteins themselves. If these proteins are present, the system is presumed functional, leading to an MSS designation.
MSS Status and Cancer Treatment Decisions
The diagnosis of a microsatellite stable tumor carries significant implications for both the expected course of the disease and the selection of treatment. In certain early-stage cancers, such as stage II colorectal cancer, MSS is sometimes associated with a higher chance of disease recurrence compared to its unstable counterpart. This status serves as a predictive biomarker, guiding oncologists away from therapies that are only effective for unstable tumors.
The treatment consequence of MSS status relates to immunotherapy, specifically the use of immune checkpoint inhibitors. MSS tumors respond poorly, or not at all, to these treatments when used alone. This resistance is due to the underlying biology of the stable tumor, which is characterized by a low tumor mutational burden (TMB). Because the DNA repair system is intact, MSS tumors accumulate far fewer genetic mutations than unstable tumors.
The low mutation rate results in the production of few neoantigens, which are unique proteins that the immune system can recognize as foreign. Without these neoantigens, the tumor is effectively “invisible” to the patient’s T-cells, leading to an immune-excluded or “cold” tumor microenvironment. Therefore, single-agent immunotherapy lacks the necessary targets to mount a sustained and effective anti-tumor response in most MSS patients.
Given the resistance to standalone immunotherapy, the standard treatment pathways for MSS tumors prioritize conventional approaches, such as chemotherapy and targeted therapy. For many common MSS cancers, a fluorouracil-based chemotherapy regimen is often the foundation of treatment. Furthermore, for metastatic MSS cancers, testing for additional biomarkers like KRAS, NRAS, BRAF, and HER2 is crucial to identify specific genetic targets for personalized drug development.
Research is actively focused on overcoming the immune resistance of MSS tumors, often through combination therapies. Strategies include combining immune checkpoint inhibitors with chemotherapy or targeted drugs, such as tyrosine kinase inhibitors. The goal of these combinations is to turn the “cold” MSS tumor into a “hot” one by enhancing T-cell infiltration and increasing the visibility of the cancer cells to the immune system.