Microsatellite instability (MSI) has been described for several cancers, especially for colorectal cancer. It is caused by mutations in or silencing of mismatch repair genes and leads to the accumulation of slipping frameshift mutations. It appears to be a very efficient way of transformation and tumor progression and one would expect that it might play a role in all cancers, but it doesn't. MSI even accounts for only 15% of colorectal cancer. I see two possibilities:
i) other mechanisms (signaling pathway mutations, chromosomal instability) might occur with a higher probability than MSI
ii) the cause of MSI, MMR gene mutation or silencing, might rely on conditions or factors not present in non MSI cancers.
If you see other possible explanations or if you are aware of evidence favoring one or the other explanation, please share it with me.
Ulrich,
I think this is a very interesting question, and I commend you on the thought put into it. I believe the answer to your question may have to do with a phenomenon similar to reason that some gene fusion products and even mutations tend to be exclusive of one another in certain types of cancers. Mutations by default tend to be harmful to a cell in terms of its survival and overall health. Thus when a mutation occurs, say something like a K-Ras mutation, the cell is has enhanced proliferative potential that continues to be held in check by the cell cycle regulating machinery. At this point the cell is not malignant, and due to the extra stress placed on the cell by the mutation, it is on the verge of crisis due ROS or metabolic needs or any other variety of means. If a second driver mutation were to occur with the cell in this state that checkpoint machinery would either correct the cellular processes so that the cell could survive or would cause the cell to undergo apoptosis. Even without this checkpoint machinery, it is likely that the stress placed on the cell by the two driver mutations (assuming that it is additive) would be fatal to the cell. In the case that the K-Ras mutation is not followed by a second driver mutation but rather a mutation that disrupts the cell cycle regulatory machinery of the cell, then the cell would be allowed to proliferate uncontrollably and thus become malignant but because of the first mutation, the cell would still be in a state of decreased health.
Now if you consider MSI in the context of cancer but outside of the context of something like Lynch Syndrome (hereditary) then you can see that a somatic mutation affecting MMR genes would result in the rapid accumulation of mutations, yet there is a high probability that these mutations could result in a fatal amount of cell stress and thus prevent the development of cancer via selective pressure against those cell bearing multiple mutations. Thus it is unlikely that the sporadic mutation of MMR pathways would result in the DNA damage in the proper place and sequence (temporally) that would result in the formation of a viable malignant clone. To contrast this with the something like Lynch syndrome in which the MMR pathway is disrupted in a hereditary way. Thus this disruption is present throughout the body not occurring sporadically. Because of this, there is a much larger population of cells that can greatly enhance the probability that a malignant clone will develop from the initial condition of having the disrupted MMR pathway.
My question after considering this is Lynch syndrome has a tendency to cause multiple different types of cancer, but it is clear that colon cancer is the most predominant form caused by this set of mutations; Why? Is it from the exposure of the colon to a large variety of potentially harmful molecules from the diet for an extended period or is from the simple fact that the turn over rate of the cells of the colon is quite high, or is it the environment of colon which is susceptible to inflammation or the specific genomic programs that cells of the colon run that other cells of the body do not?
Andrew,
very interesting. But still some 15% of sporadic colorectal cancers have MSI and it appears to be caused by both MMR gene mutations (identified by exome sequencing) or by MLH1 silencing (methylation). The fact that the high mutation rate may eventually kill the cell is reflected by the better prognosis of MSI colorectal cancers as compared to non-MSI cancers. So, if MSI can be pro-tumoral in 15% of sporadic CRCs and in endometrial cancer (EC), why not in other cancers? Here you propose exposure to carcinogens (which would be less the case for EC). Perhaps one of the strongest carcinogens is inflammation that is elevated for both, CRC and EC.
Dear Baolin, I think 15% is simply what has been observed, you might find details in Fearon, E. R. (2011). Molecular genetics of colorectal cancer. Annual Review of Pathology, 6, 479–507. doi:10.1146/annurevpathol- 011110-130235. See also my article on CRC that I attach.
To answer your question concerning other cancers the best way would be to look into the TCGA data. There are MSI cases in all cancer types but they are much less frequent. Still, this could be important for immune checkpoint blocker therapy.
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