A
recent study from the University of Washington in Seattle indicates
that microsatellite instability, classically associated with colorectal,
stomach, and endometrial cancers, is a much more extensive phenotype
than previously appreciated. The researchers developed MOSAIC, a method
to assess microsatellite instability on a comprehensive, genome-wide
scale, and identified tumors positive for this phenotype in 14 of 18
different cancers evaluated.
Microsatellite instability (MSI), the spontaneous loss or
gain of nucleotides from repetitive DNA tracts, is a diagnostic
phenotype for gastrointestinal, endometrial, and colorectal tumors, yet
the landscape of instability events across a wider variety of cancer
types remains poorly understood. To explore MSI across malignancies, we
examined 5,930 cancer exomes from 18 cancer types at more than 200,000
microsatellite loci and constructed a genomic classifier for MSI. We
identified MSI-positive tumors in 14 of the 18 cancer types. We also
identified loci that were more likely to be unstable in particular
cancer types, resulting in specific instability signatures that involved
cancer-associated genes, suggesting that instability patterns reflect
selective pressures and can potentially identify novel cancer drivers.
We also observed a correlation between survival outcomes and the overall
burden of unstable microsatellites, suggesting that MSI may be a
continuous, rather than discrete, phenotype that is informative across
cancer types. These analyses offer insight into conserved and
cancer-specific properties of MSI and reveal opportunities for improved
methods of clinical MSI diagnosis and cancer gene discovery.
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