Tae-Min Kim,1,2 Peter W. Laird,3 and Peter J. Park1,4,*
1Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
2Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
3USC Epigenome Center, Department of Surgery and of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
4Informatics Program, Children’s Hospital Boston and Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
*Correspondence: Peter J. Park
Microsatellites.simple tandem repeats present at millions of sites in the human genome.can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and hole-genome sequencing data. RecurrentMSI events in coding sequences showed tumor type specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wild-type alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in
euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization.