Most low-level microsatellite instability in colorectal cancers can be explained without an elevated slippage rate.
Many cancers show a low level of microsatellite slippage and are labelled MSI-L (microsatellite instability--low). However, it is unclear whether this slippage can be attributed to some underlying genetic change that results in a mutator phenotype, analogous to mismatch repair deficiency in MSI-H cancers, or whether the apparent instability is the result of relatively frequent normal somatic slippage. Here, we have used a mathematical model of microsatellite slippage during cancer growth to estimate the degree of microsatellite slippage expected in a cancer due to normal somatic slippage. We compared the model to the slippage observed in 42 non-MSI-H cancers that were macro-dissected into four distinct regions and genotyped at N = 9 microsatellite loci. When the slippage rate was set at mu = 10(-5) per locus per division, ten cancers showed a level of slippage in at least one region that was too severe to be expected from normal somatic slippage alone, suggesting that these cancers had acquired MSI-L. Only one of these ten cancers had putative MSI-L in all four regions. When we considered a slightly higher slippage rate of mu = 5 x 10(-5), none of the cancers showed a degree of slippage that could not be reasonably explained by normal somatic slippage. Counting the number of 'unstable' loci was a poor indicator of putative MSI-L status. We conclude that most low-level microsatellite instability in colorectal cancers can be explained without requiring an elevated slippage rate during neoplastic development, and hence there is little evidence for a discrete MSI-L group of cancers. Putative MSI-L status is indicated by the presence of at least one locus that has multiple alleles that differ by at least five motif repeats from the germline. If an underlying genetic change does cause MSI-L, it appears to be a relatively uncommon event that occurs late in oncogenesis.
Graham
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Centre of Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, Gower St, London, WC1E 6BT, UK. trevor.graham@ucl.ac.uk
Halford
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Page
K M
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Tomlinson
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IP
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D008957:Models, Genetic; D016133:Polymerase Chain Reaction / Q000379:methods