What Is MSS Cancer and How Is It Treated?

Microsatellite Stable (MSS) cancer refers to a tumor’s genetic characteristic, indicating stability in specific DNA sequences. Understanding this status is important for tailoring diagnostic approaches and treatment strategies, as it helps doctors determine how a tumor might behave and what therapies could be most effective.

Understanding Microsatellite Status

Microsatellites are short, repetitive segments of DNA found throughout an organism’s genome. In normal cells, these microsatellites are maintained with high fidelity during DNA replication, meaning their lengths remain stable.

The stability of these sequences is maintained by a process called DNA mismatch repair (MMR), which corrects errors that occur during DNA replication. When the MMR system functions properly, microsatellite sequences in a tumor remain unchanged, and the tumor is classified as Microsatellite Stable (MSS). If the MMR system is deficient, these repetitive sequences can accumulate changes in length, a condition known as Microsatellite Instability (MSI).

Distinguishing MSS from MSI Cancer

The primary difference between MSS and Microsatellite Instability (MSI) cancers lies in the functionality of their DNA mismatch repair (MMR) system. MSS tumors possess a proficient MMR system, meaning their cells effectively correct DNA replication errors, resulting in stable microsatellite sequences. This proficiency leads to a lower number of genetic mutations within the tumor.

Conversely, MSI tumors exhibit a deficient MMR system, often due to mutations or other genetic alterations in MMR genes like MLH1, MSH2, MSH6, or PMS2. This deficiency leads to a high accumulation of mutations in microsatellite regions, making the tumor genetically unstable. MSI-High tumors are frequently associated with hereditary cancer syndromes like Lynch syndrome, where a germline mutation in an MMR gene is passed down through generations. MSS tumors are the more common type, representing approximately 80-85% of all colorectal cancers and are generally considered sporadic cases.

Implications for Treatment

Knowing a tumor’s MSS status is an important factor in guiding treatment decisions, particularly for colorectal cancer and other solid tumors. MSS tumors do not respond well to certain immunotherapies, like immune checkpoint inhibitors. This is because MSS tumors have a lower tumor mutational burden and fewer neoantigens, abnormal proteins the immune system can recognize.

For MSS cancers, standard treatment approaches include chemotherapy, targeted therapies, and radiation. For instance, fluorouracil-based chemotherapy is a common treatment for MSS colorectal cancer. While single-agent immunotherapies have shown limited clinical activity in MSS tumors, ongoing research explores combination therapies. Studies are investigating combining immune checkpoint inhibitors with other drugs, such as tyrosine kinase inhibitors or chemotherapy, to enhance the immune response in MSS tumors. Phase I trials have shown promising results for certain immunotherapy combinations in MSS colorectal cancer, leading to ongoing phase III trials.

Prognosis and Outlook

The prognosis for MSS cancers can be less favorable, especially in advanced stages, compared to MSI-High tumors. This is largely due to their lower mutation burden and their lack of response to certain immunotherapies that are highly effective for MSI-High tumors. Patients with MSS colorectal cancer may have a higher risk of recurrence.

However, prognosis varies greatly depending on several factors, including the specific type of cancer, the stage at diagnosis, and individual patient characteristics. While MSI-High tumors are often associated with a more favorable prognosis in early stages, the outlook for MSS cancers is continually being refined through ongoing research into new therapeutic strategies.

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