The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes
Menée dans le cadre du projet "The Cancer Genome Atlas" à partir de 277 échantillons tumoraux prélevés sur des patients atteints d'un cancer du côlon-rectum ou de l'endomètre, cette étude analyse la prévalence et les conséquences fonctionnelles d'une instabilité des microsatellites
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 whole-genome sequencing data. Recurrent MSI 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. "Analysis of genome sequencing data provides a genome-wide view of MSI in human cancers "Genes affected by MSI show tumor type specificity "Recurrent MSI in coding regions shows a high frameshift-to-in-frame ratio "MSI frequency is associated with chromatin organization and nucleosome positioning A comprehensive analysis of data from The Cancer Genome Atlas provides a panoramic view of microsatellite instability (MSI) in colorectal and endometrial cancers, showing tumor-type-specific effects and a role for chromatin organization in determining the frequency of MSI.