Microsatellite Instability (MSI)
- Microsatellites are parcels of DNA code
- Microsatellite Instability in those parcels (MSI)
- Mismatch Repair (MMR) our body’s DNA spell checker
- Deficient Mismatch repair (dMMR) means failure of the spell checker
Microsatellite Instability occurs when the strings of DNA contained within the microsatellites, replicate incorrectly creating errors in our DNA code.
MSI is described as follows
- MSI-high: (MSI-H) occurs if two or more microsatellite markers show instability
- MSI-low: (MSI-L) occurs if there is only one marker unstable
- MSI-Stable : (MSS) results when all the five microsatellite markers are stable
Reporting often describes MSI as follows
- MSI-h > 30%
- MSI-L <30%
- MSS – 0% instability
MMR the Spell Checker
- MMR – means all genes are functioning / expressing correctly
- dMMR – when one or more genes are not expressing and correctly
There are 4 primary MMR genes are MLH1, MSH2, MSH6, and PMS2
Think of these genes as our body’s spell checkers, their job is to express proteins that fix/repair DNA replication errors as they occur. This is a normal function within our body.
What is spell checking?
- Errors occur often in our DNA replication process.
- Microsatellites are parcels that contain strings of our pre-made dna code – the code that makes us – us!
- This replication process is constant and errors are normal
- When all 4 MMR genes are expressing proteins (spell checkers), then this is described as MMS (Stable).
When one or more of these genes fail to express their proteins (spell checkers) this means the MMR process is now deficient and is not correcting all DNA mistakes as they occur. This then leads to the accumulation of DNA replication errors within the microsatellites creating microsatellite instability.
Uncorrected errors lead to accumulations of defective cells that cluster and can form cancer mutations.
Immunotherapy and MSi-High
The MSi-high status has so far proven to perform best with Checkpoint Inhibitor Immunotherapy treatments, so this is the primary testing objective.
Testing for MSi-high
There are 2 primary testing methods to determine this, both require a tissue sample (biopsy)
- IHC fast efficient and inexpensive
- Molecular profiling more expensive and slower
- Blood Profiling – Still in early stage
IHC and Molecular test accuracies a 92% and 95% with blood much lower at this stage (2019)
For the purpose of discovering if you are a match for Check Point Immunotherapy, the IHC test is most logical. If via the IHC test you do not have the MSi-high as a biomarker then pursue the full “Molecular Profiling” to discover a full road map of your tumors make up and what mutations are driving your cancer. This can then be matched up with known treatments globally.
IHC Test Description
Immunohistochemistry Test – fast and Efficient (3 -5 days) see Testing Page
What you testing for is MSi-high result, as immunotherapy responds well to this.
What do Microsatellites do?
They are the containers that hold our repetitive sequences of nucleotides (DNA code).
What are Nucleotides?
- Nucleotides are sequences of our DNA code. (Sequence repeats)
- Nucleotides are our “DNA Building Blocks”
- Nucleotides typically have 2 to 7 different types of pre programmed sequences of repeat code –
- Each sequence can contain between 2 -25 characters (string or stretch of code) – see diagram below.
- Nucleotide sequences continually replicate.
- Everyone has different pre programmed sequences.There can be hundreds of different code sequences.
The Nucleotide replication process can often go wrong
The MMR expressed proteins correct these spontaneous errors as they occur. When our MMR spell Checker is compromised or weakened then inconsistencies in the Microsatellites Nucleotides repeats over and over, this is when cancers can form.
Lab testing (IHC) can easily discover this when comparing healthy cell numbers or sequences, with cancer cells. If a difference is identified, then this is referred to as “microsatellite instability”.
Samples of Nucleotide code sequences contained within a microsatellite are supposed to replicate exactly the same in tandem.
Scott Paulson MD
Extract from CURE who spoke with Scott Paulson, M.D. medical oncologist with Texas Oncology, an affiliate of The US Oncology Network, to break down exactly what MSI-H status is, and the effects it may have on certain malignancies. Full Article link
MSI-high tumours form a well-defined group with distinct clinicopathologic features (more easily identifiable) which characterizes an overall better long-term prognosis.
MSI-H is a feature of cancer’s genetic coding, which results in it behaving and “looking” a certain way on a microscopic level. Due to defects in the way that DNA in the cancer cells repairs itself, it creates changes and mutations to normal body cells that can eventually let them turn into cancer. However, these cells become so abnormal, because of this feature, that the immune system, which is used to protecting the body against bacteria and viruses and other foreign invaders, can actually look at the cancer and recognize that something is very wrong. This can call the body’s normal defenses against invaders to try to attack the cancer.