A microsatellite stable (MSS) tumor refers to a type of cancer where cells exhibit genetic stability. This means that repetitive DNA sequences within the tumor, known as microsatellites, remain largely unchanged. This status is determined through diagnostic testing and provides information about the tumor’s biological characteristics.
Understanding DNA Repair and Stability
Microsatellites are short, repetitive segments of DNA, typically 1 to 6 base pairs long, scattered throughout the human genome. These regions are particularly prone to errors during DNA replication due to their repetitive nature.
To counter these replication mistakes, cells possess a sophisticated mechanism called the DNA Mismatch Repair (MMR) system.
The MMR system acts like a genetic “spell-checker,” identifying and correcting incorrectly paired bases or small insertions and deletions that arise during DNA copying. When this proficient MMR (pMMR) system works correctly, it ensures microsatellite sequences remain consistent and unchanged, leading to microsatellite stability.
Microsatellite Stable Versus Microsatellite Instable Cancers
The distinction between microsatellite stable (MSS) and microsatellite instability-high (MSI-H) cancers lies in the functionality of their DNA Mismatch Repair (MMR) system. While MSS tumors have a proficient MMR system, MSI-H tumors result from a faulty or deficient MMR (dMMR) system. This deficiency leads to a high accumulation of genetic mutations within the microsatellite regions in MSI-H tumors.
The high mutation rate in MSI-H tumors produces many abnormal proteins, called neoantigens, making these tumors highly visible or “hot” to the immune system. In contrast, MSS tumors, with their intact MMR system, accumulate far fewer mutations and thus fewer neoantigens, making them immunologically “cold” or less easily recognized by the body’s immune defenses.
Testing and Associated Cancer Types
Determining a tumor’s MSS or MSI status is a routine and important part of cancer diagnostics for several cancer types. This status is a particularly crucial biomarker in colorectal cancer, where approximately 80-85% of cases are found to be MSS. Endometrial and gastric cancers are also common types where MSS/MSI status is frequently assessed.
Several laboratory methods determine microsatellite status, typically using a tumor biopsy. Immunohistochemistry (IHC) checks for specific MMR proteins (MLH1, MSH2, MSH6, PMS2). Molecular tests like Polymerase Chain Reaction (PCR) or Next-Generation Sequencing (NGS) directly analyze microsatellite sequence length and integrity. Circulating tumor DNA (ctDNA) from a blood sample can also be used for testing when tumor tissue is unavailable.
Treatment Approaches for Microsatellite Stable Tumors
The “cold” immunological profile of microsatellite stable (MSS) tumors influences their response to certain therapies. Due to fewer mutations and reduced immune visibility, MSS tumors generally show a poor response to immune checkpoint inhibitors, immunotherapy drugs that unleash the body’s immune system against cancer cells. This limited efficacy has been observed in studies for MSS colorectal cancer.
Standard-of-care treatments for MSS cancers involve conventional systemic therapies. Chemotherapy, often fluorouracil-based, remains a primary treatment option for many MSS tumors, including colorectal cancer. Targeted therapies are also employed, which specifically block growth signals or pathways within cancer cells. These include anti-VEGF agents, which inhibit new blood vessel formation, or anti-EGFR agents, which target epidermal growth factor receptors on cancer cell surfaces.
Ongoing research aims to make “cold” MSS tumors more susceptible to immunotherapy. Scientists are exploring various combination strategies, such as pairing immunotherapy with chemotherapy, radiation, or targeted therapies, to enhance the immune response. Studies investigate combining immune checkpoint inhibitors with anti-angiogenic drugs or anti-EGFR agents, hoping to alter the tumor microenvironment and improve T-cell infiltration. These emerging approaches expand effective treatment options for patients with MSS tumors.