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October 4, 2016

Microsatellite Instability Tied to Cancer Progression and Survival

  • The genome is littered with microsatellites, short stretches of repetitive DNA that are known to lose or gain nucleotides in certain cancers. Despite this connection between microsatellites and cancer, microsatellites have not been systematically surveyed—until now. A new study has examined more than 200,000 microsatellite sites across 18 cancer types, going far beyond previous studies, which mainly looked at relatively few microsatellites in just a handful of cancer types.

    The new study, completed by scientists based at the University of Washington Health Sciences/UW Medicine, suggests that microsatellites play a greater role in cancer than previously thought. The UW Medicine team found that most cancer types have examples of tumors with microsatellite instability (MSI), a tendency to lose or gain nucleotides during DNA repair processes. The scientists also learned that different cancer types had distinct patterns of mutation across their microsatellites.

    Details appeared October 3 in the journal Nature Medicine, in an article entitled, “Classification and Characterization of Microsatellite Instability across 18 Cancer Types.” The article describes how the UW Medicine team explored MSI across malignancies by examining 5930 cancer exomes from 18 cancer types at more than 200,000 microsatellite loci. To accomplish this feat, the scientists obtained sequencing information from a massive genome database storehouse, The Cancer Genome Atlas. Ultimately, the scientists constructed a genomic classifier for MSI and identified MSI-positive tumors in 14 of the 18 cancer types tested.

    “We 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,” wrote the article’s authors. “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.”

    Over half of the MSI sites they uncovered were within or near so-called "cancer genes"—genes that that are implicated in cancer development and progression. This finding suggests the microsatellite mutations may be causing these genes to malfunction. The other half of the MSI sites were not located in or near known cancer genes, but because these mutations were frequent among the different tumor types, they could possibly play a yet undetermined role in cancer.

    "These sites may be pointing to new cancer genes that we haven't previously known about," said senior author Stephen J. Salipante, University of Washington assistant professor of laboratory medicine.

    The researchers also observed a paradox: Patients who had tumors with comparatively more unstable microsatellite sites tended to survive longer.

    Dr. Salipante and his colleagues hypothesize that cancers cells with relatively high numbers of MSI events are producing more mutated proteins of all kinds, not just cancer genes. These mutated proteins draw the attention of the immune system and trigger immune attacks that slow tumor progression.

    "This suggests that by analyzing the entire genome of a tumor instead of just a few microsatellite sites as is done now, it will be possible to identify those patients with tumors that will most likely to respond to new cancer immunotherapies," noted Dr. Salipante.

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