Microsatellite Instability Cancer

Microsatellite instability is a unique change in cancer cells that occurs when the body’s normal DNA repair system stops working properly, leading to genetic errors that accumulate in tumor cells and affect how cancer responds to treatment.

Table of contents

• What is Microsatellite Instability?
• How Microsatellite Instability Occurs
• Types of Microsatellite Instability
• Cancers Affected by Microsatellite Instability
• Detection and Testing
• Treatment Implications

What is Microsatellite Instability?

To understand microsatellite instability, it helps to first know what microsatellites are. Microsatellites are short, repeating sections of DNA scattered throughout our genetic code. They are also called Short Tandem Repeats or Simple Sequence Repeats. These sections consist of repeated sequences of 1 to 6 small building blocks called nucleotides^[7].

Microsatellites usually comprise 6 to 10 base pairs and can occur thousands of times throughout the entire DNA code. They are widely distributed in the human genome and mostly located near regions that contain genes, though they can also be found in other areas^[5]. These repeating sections make up approximately 3% of the human genome^[3].

Microsatellite instability (MSI) refers to a condition where the length of these microsatellite sequences changes. This happens when mistakes occur during DNA copying and are not properly fixed. Microsatellite instability is the presence of alternate sized repetitive DNA sequences that are not present in the corresponding normal DNA^[3].

How Microsatellite Instability Occurs

Our bodies have a built-in system to fix mistakes that happen when DNA copies itself. This system is called mismatch repair (MMR). The mismatch repair system constantly scans for any mistakes in DNA copies and corrects them^[5].

When cells divide to make new cells, DNA must duplicate itself. During this process, the bases (the building blocks of DNA) can sometimes be matched incorrectly. For example, adenine might pair with cytosine or guanine instead of its normal partner, thymine. This can happen if the two DNA strands become misaligned^[5].

In cancer cells, problems can develop with the mismatch repair system. When MMR genes are lacking or defective in tumor cells, the repair process cannot work properly. This condition is called deficient DNA mismatch repair (dMMR). When the repair system fails, mistakes in microsatellite regions accumulate, and the microsatellites become unstable^[7].

The defects in the mismatch repair system can happen in two main ways. In most cases, the change occurs during a person’s lifetime through a process called methylation, where a gene called hMLH1 becomes turned off without an actual mutation in the gene itself. These are called sporadic cases and make up most MSI cancers^[7].

In other cases, people inherit a mutation in one of the MMR genes from their parents. This inherited condition is called Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer. Lynch syndrome is an autosomal dominant disorder, meaning that inheriting one mutated gene from either parent is enough to increase cancer risk^[7].

Types of Microsatellite Instability

Based on how frequently microsatellite instability appears in a tumor, cancers can be classified into three types^[7]:

• Microsatellite Instability-High (MSI-H): Tumors show instability in many microsatellite markers
• Microsatellite Instability-Low (MSI-L): Tumors show instability in only a few microsatellite markers
• Microsatellite Stable (MSS): Tumors show no microsatellite instability

In current clinical practice, doctors tend to group MSI-L and MSS together as one category, since they behave similarly. The main distinction that matters for treatment decisions is between MSI-H tumors and those that are not MSI-H^[7].

Tumors are often referred to as having an “MSI status,” meaning they are described as either MSI (microsatellite instable) or MSS (microsatellite stable)^[4].

Cancers Affected by Microsatellite Instability

Microsatellite instability is found in several types of cancer, though it is most common in certain tumor types. Approximately 15 to 20% of colorectal cancers display microsatellite instability^[3].

MSI-H is found in about 15% of colorectal carcinomas. A high proportion of colon cancers arising in patients with Lynch syndrome have high MSI, and a smaller percentage of colon cancers not associated with Lynch syndrome also have high MSI^[8].

Beyond colorectal cancer, microsatellite instability may also be found in other types of cancer. Around 1 in 3 endometrial cancers, and 1 in 7 colorectal, stomach, and ovarian cancers are MSI-high^[14]. It may also be found in cancers of the breast, prostate, bladder, and thyroid^[8].

MSI is found most often in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer^[8]. The presence of microsatellite instability is found in sporadic colon, gastric, sporadic endometrial and the majority of other cancers^[3].

Detection and Testing

Testing for microsatellite instability is performed on tumor tissue. The test looks for differences in the length of certain sections of DNA to determine whether the cancer cells have a working DNA repair system^[8].

There are different methods to detect microsatellite instability. Testing can be done by examining the microsatellite sequences themselves or by testing the mismatch repair proteins. MSI may be tested by immunology or genetic testing. Only genetic testing results will specify whether the MSI is low or high^[8].

Testing for mismatch repair is usually done by a method called immunohistochemistry (IHC). The most common markers tested are MLH1, MSH2, MSH6, and PMS2^[8].

Advanced technology called next-generation sequencing can also detect mutations in all genes associated with mismatch repair, including microsatellite instability^[5].

Microsatellite instability may be recorded for all stages of cancer, though it is primarily performed for invasive cancers. Results from tumor tissue at the primary site, or even from tissue that has spread to lymph nodes or other areas, may be used for testing^[8].

A physician’s statement about MSI can be used when no other information is available^[8].

Treatment Implications

Knowing whether a cancer has microsatellite instability is important because it affects treatment decisions. Determination of MSI status in cancer has prognostic and therapeutic implications^[3].

Patients with MSI-H tumors have been reported to benefit from immunotherapy. With the recent development of immunotherapy drugs, researchers found that MSI-H tumors respond well to this type of treatment. The FDA approved an immunotherapy drug called Keytruda to treat MSI-H/MMR deficient patients^[7].

Patients with colorectal cancers that are MSI-high may have better response to surgery and improved survival compared to those with other types of colorectal cancer^[8]. MSI is a useful prognostic marker, meaning it helps predict how the cancer will behave and how well treatment will work^[8].

The presence of microsatellite instability in a tumor can change the type of therapy a doctor chooses to provide^[5]. The more information doctors have about a specific tumor, including its MSI status, the more effective treatment can be^[5].

MSI can be used as a genetic instability marker for tumor detection and classification^[7]. This information helps doctors plan the best treatment approach for each individual patient.