XThe landscape of microsatellite instability in colorectal and endometrial cancer genomes

Tae Min Kim; Peter W. Laird; Peter J. Park

doi:10.1016/j.cell.2013.10.015

XThe landscape of microsatellite instability in colorectal and endometrial cancer genomes

Tae Min Kim
, Peter W. Laird
, Peter J. Park

Department of Medical Informatics

Research output: Contribution to journal › Article › peer-review

315 Scopus citations

Abstract

Summary 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.

Original language	English
Pages (from-to)	858
Number of pages	1
Journal	Cell
Volume	155
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2013.10.015
State	Published - 7 Nov 2013

Bibliographical note

Funding Information:
We thank The Cancer Genome Atlas Research Network for generating the data used in this work. We also thank the members of the Park laboratory (especially Drs. Eunjung Lee, Nils Gehlenborg, and Semin Lee) and Dr. Peter Kharchenko for providing comments on the manuscript, Dr. David Wheeler for helpful discussions, and the Research Information Technology Group at Harvard Medical School for providing computational resources. This work was supported by grants from the National Institutes of Health (R01 GM082798 and U24CA144025 to P.J.P.) and the National Research Foundation of Korea (2012R1A5A2047939 to T.-M.K.).

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10.1016/j.cell.2013.10.015

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title = "XThe landscape of microsatellite instability in colorectal and endometrial cancer genomes",

abstract = "Summary 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.",

author = "Kim, \{Tae Min\} and Laird, \{Peter W.\} and Park, \{Peter J.\}",

note = "Funding Information: We thank The Cancer Genome Atlas Research Network for generating the data used in this work. We also thank the members of the Park laboratory (especially Drs. Eunjung Lee, Nils Gehlenborg, and Semin Lee) and Dr. Peter Kharchenko for providing comments on the manuscript, Dr. David Wheeler for helpful discussions, and the Research Information Technology Group at Harvard Medical School for providing computational resources. This work was supported by grants from the National Institutes of Health (R01 GM082798 and U24CA144025 to P.J.P.) and the National Research Foundation of Korea (2012R1A5A2047939 to T.-M.K.). ",

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T1 - XThe landscape of microsatellite instability in colorectal and endometrial cancer genomes

AU - Kim, Tae Min

AU - Laird, Peter W.

AU - Park, Peter J.

N1 - Funding Information: We thank The Cancer Genome Atlas Research Network for generating the data used in this work. We also thank the members of the Park laboratory (especially Drs. Eunjung Lee, Nils Gehlenborg, and Semin Lee) and Dr. Peter Kharchenko for providing comments on the manuscript, Dr. David Wheeler for helpful discussions, and the Research Information Technology Group at Harvard Medical School for providing computational resources. This work was supported by grants from the National Institutes of Health (R01 GM082798 and U24CA144025 to P.J.P.) and the National Research Foundation of Korea (2012R1A5A2047939 to T.-M.K.).

PY - 2013/11/7

Y1 - 2013/11/7

N2 - Summary 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.

AB - Summary 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.

UR - https://www.scopus.com/pages/publications/84887924524

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DO - 10.1016/j.cell.2013.10.015

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AN - SCOPUS:84887924524

SN - 0092-8674

VL - 155

SP - 858

JO - Cell

JF - Cell

IS - 4

ER -

XThe landscape of microsatellite instability in colorectal and endometrial cancer genomes

Abstract

Bibliographical note

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