The acronym "MSI" has come up in a number of posts concerning the use of immunotherapy, specifically with pembrolizumab (trade name Keytruda). Never having heard of MSI before I looked it up in the Wikipedia. I did not read it in great depth and would be hard pressed to explain it in great scientific detail, but for those who at least want to know what it's about, here's my interpretation.
For those who have read about DNA and want to take a shot at understanding the underlying science - MSI stands for "Microsatellite Instability" and is explained here: ( en.wikipedia.org/wiki/Micro... ), and more about microsatellites can be found here: (en.wikipedia.org/wiki/Micro... ).
A summary of my understanding from the articles is that microsatellites are short sequences (strings of one to as many as ten "base pairs") of DNA that repeat many times but occur outside of the tiny percentage of DNA that constitutes our genes. They don't, themselves, have anything to do with cancer but, because they tend to mutate more often than other areas of DNA, a comparison of the microsatellites in a person's tumor cells with ordinary cells can offer evidence that we have a lot of unrepaired DNA mutation going on. In other words, when our prostate cells replicate, mistakes are happening that would normally be fixed by our DNA repair proteins, but are not being fixed. That means that our cancer is mutating often and is likely to develop defenses against treatments relatively quickly. Apparently, Keytruda (and perhaps other drugs too) can recognize such abnormal cells and flag them for destruction.
The MSI test is used to determine whether Keytruda has a good chance of helping, or whether treating a patient with Keytruda would likely just waste time and add side effects without smacking down the cancer.
Alan
PS:
For those of us who think that medical science is composed of a bunch of boobies who don't understand obvious truths about cancer - try reading the two Wikipedia articles cited above and, when you find something you don't understand, look it up. It may give you some idea of the incredible difficulties in understanding cancer biology. I have great respect for rocket scientists but I think cancer biology is every bit as hard as rocket science.
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AlanMeyer
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Great explanation! One amplification - Keytruda is only approved for MSI when it is high. While you are on a roll, don't stop there - Keytruda is also approved for dMMR (deficient mismatch repair). Also, the identification of MSH2 and MSH6 as biomarkers of it, and their detection by IHC or genomic tests.
I agree so much that cancer biochemistry is not for the fainthearted. When I read simplistic explanations on this site (e.g., "get inflammation as low as possible"), it reminds me that a little knowledge can be a truly dangerous thing.
So far over my head I feel that I'm 100' under water.
Thanks for posting this. I’d like to know more about DNA repair molecules—what strengthens them, what weakens them? They sound rather key to this whole cancer business.E
The MMR (mismatch repair) that our bodies typically do has certainly got to be a part of the solution to this puzzle. I wonder if those other’Rocket Scientists’ who developed CRISPR gene editing technology are looking at cancer yet. CRISPR sounds like it functions a lot like MMR to a lay person like myself
Your question is a difficult one to answer, and not just for an inexpert person like me. Cancer biology is terribly complicated and there are still huge unknowns. Damage to DNA repair mechanisms can enable dangerous mutations to occur more frequently. However on the other hand, greater damage to the DNA in tumor cells can help provide a target for a therapeutic drug like Keytruda to locate and flag tumor cells for destruction. I think it's going to take at least a few more decades before the cancer researchers get enough understanding of all of the factors to make clear recommendations.
For what it's worth, here is a web page written by the U.S. National Cancer Institute (NCI) that lays out their view of the existing evidence for the influence of diet on prostate cancer: cancer.gov/about-cancer/tre...
NCI is very conservative in its recommendations. They only say a food or supplement should be taken or avoided if they have scientifically valid evidence supporting their statement, ideally from a well designed clinical trial. A scientist publishing a claim that six mice that he fed XYZ lived longer than six mice from whom he withheld XYZ, would not be accepted by the NCI as evidence for eating XYZ.
That is a "patient" version of the document. A more technical "health professional" version is also available (there's a link to it in the patient version) if you want more technical detail on the evidence.
Thanks Alan, I've started to read through the list on the link you sent me. And I've looked at those countries that have low PC vs high PC--most of them in Asia and thought about the diet difference.
My husband has been a vegetarian from about age 17 --with herbal supplements, etc. . But his profession has been in underwater construction and demolition--bridges, tunnels, and the sort. He is a commercial diver who also does "top-side" work. That said he was at Ground Zero in the immediate aftermath and then involved with moving the debris later on.
He has a very aggressive form of PC--it arrived like a shot in the dark. So I think it's a fair assessment thinking that we are living in a stew of industrial waste and chemicals that contribute to dna malfunction.I guess we have a ways to go yet before it gets sorted out. Best wishes to you.
In most cases, I don't think that oncologists can tell what triggered the onset of cancer. Some types of cancer, like lung cancer, have clear connections to environmental issues. The rate of lung cancer is said to be 15 times higher among smokers than non-smokers. But, as I understand it, dietary and environmental causes of prostate cancer have not been clearly identified.
Cancer is strongly associated with growing old. DNA mutations accumulate over many years, even in people with vegetarian diets and good health habits. A tiny number of mutations occur in every person over time and it's mostly random where they occur. In some people it may be almost all in DNA that doesn't occur in our genes. In others there may be random mutations in critical genes in prostate cells, or breast cells, or pancreas cells, or brain cells, or whatever, that lead to deadly disease. Inheritance apparently plays a role and men whose fathers had prostate cancer are more at risk than those without that issue.
I don't know that my analysis helps at all. However I do think you're doing the right thing in researching what you can do in addition to medical treatment to restrain the cancer. I'm not sure what more to say except - I wish you both the best of luck.
I remember reading that people were talking about launching a "war on cancer" in the 60's, but nobody knew how to do it. Some leading scientists were asked how they would spend a billion dollars, or whatever, to cure cancer, and they didn't have answers. I don't think we even knew in those days that DNA mutations were involved.
But, as you say, at least we knew what to do to get to the moon :^)
Thank you for this, Alan. Few of us are educated enough to understand the biochemistry, but you help us understand the general concept and what is involved. Without many MSIs showing up I've not been offered Keytruda, and I've understood there's no reason to apply a "fix" to a specific problem one does not have. But it's always good to have more information - and someone knowledgeable enough to explain it!
Thank you Alan for this explanation, since my husbands life was saved with finding out he had this and treated with Keytruda it helps to know the behind the scenes work that went on in his body. I may have heard the definition before but for others it may help give clarification and direction
Here's my take on microsatellites, mismatch repair, and mutational burden: If the immune system is to recognize the cancer as cancer, it must be sufficiently different from normal cells, as our healthy cells will mutate with time though most won't become cancer.
Keytruda, Atezolizumab, etc., are in a class of PD-L1 antibodies. I've described the PD-L1 protein as a name tag that says "I am Tom", and since my immune system doesn't want to attack Tom, it ignores cells that express PD-L1. Cancer tends to over-express PD-L1 in an attempt to hide from the immune system. Keytruda, Atezolizumab, etc,. cover up the name tag making it ineffective.
Of course, there are other mechanisms to prevent the immune system from attacking healthy cells, and if the cancer isn't sufficiently mutated, Keytruda et al won't work. As evidence, my very aggressive cancer has a low mutational burden, stable microsatellites, and is "proficient" at mismatch repair. I learned this only after Atezolizumab did nothing for me but produce side effects.
They can put a number on mutational burden: Mine is around a 1, and a value of 8 or higher means likely success PD-L1 targeted therapies. It seems instead of mutations I have a lot of whole-gene deletions and duplications, which doesn't really catch the attention of the immune system
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