Most low-level microsatellite instability in colorectal cancers can be explained without an elevated slippage rate

Area of Science:

• Oncology
• Genetics
• Cancer Biology

Background:

• Many cancers exhibit low microsatellite instability (MSI-L), but its cause remains debated.
• It's unclear if MSI-L stems from a genetic mutator phenotype or normal somatic slippage.

Purpose of the Study:

• To model microsatellite slippage in cancer growth.
• To differentiate between normal somatic slippage and a potential MSI-L genetic cause.

Main Methods:

• Mathematical modeling of microsatellite slippage.
• Analysis of 42 non-MSI-H colorectal cancers across four regions.
• Genotyping at N=9 microsatellite loci.

Main Results:

• At a slippage rate of 10⁻⁵, ten cancers showed instability exceeding normal somatic slippage, suggesting acquired MSI-L.
• At a slippage rate of 5x10⁻⁵, no cancer showed instability unexplainable by normal somatic slippage.
• Counting unstable loci was an unreliable indicator of MSI-L.

Conclusions:

• Most low-level microsatellite instability in colorectal cancers can be explained by normal somatic slippage.
• There is little evidence for a distinct MSI-L cancer group.
• If a genetic cause for MSI-L exists, it's likely a rare, late-stage event.