Characterization of clonal evolution in microsatellite unstable metastatic cancers through multi-regional tumor sequencing
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Date
2020-02
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Abstract
Microsatellites are short, repetitive segments of DNA, which become dysregulated in mismatch repair-deficient tumors with microsatellite instability (MSI). MSI has been identified in several human cancer types. Of clinical interest, microsatellite instability-high (MSI-H) tumors often exhibit increased sensitivity to immune-enhancing therapies such as PD-1 inhibition. Next-generation sequencing (NGS) has permitted advancements in MSI detection, however the evolution and heterogeneity of microsatellite changes in MSI-positive tumors remains poorly described. Furthermore, recent computational advances have enabled characterization of tumor subclones via NGS. We determined microsatellite status using MANTIS, and inferred subclonal composition and phylogeny with Canopy. We developed a simulated annealing-based method to study subclonal microsatellites and assess the evolution of MSI in the context of tumor heterogeneity. We identified three to eight tumor subclones per patient, each of which exhibited MSI-associated base substitution signatures. We noted that MSI increases over time, introducing novel mutations throughout the disease course. Some microsatellites are consistently unstable among all subclones in a patient, whereas other loci are only unstable in particular subclones corresponding to subclonal phylogenetic relationships.
Description
Health Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
bioinformatics, cancer, microsatellite instability, tumor heterogeneity, genomics