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Classification and characterization of microsatellite instability across 18 cancer types

A Corrigendum to this article was published on 01 April 2018

A Corrigendum to this article was published on 01 October 2017

This article has been updated

Abstract

Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, and colorectal tumors, yet the landscape of instability events across a wider variety of cancer types remains poorly understood. To explore MSI across malignancies, we examined 5,930 cancer exomes from 18 cancer types at more than 200,000 microsatellite loci and constructed a genomic classifier for MSI. We identified MSI-positive tumors in 14 of the 18 cancer types. We also 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. 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. These analyses offer insight into conserved and cancer-specific properties of MSI and reveal opportunities for improved methods of clinical MSI diagnosis and cancer gene discovery.

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Figure 1: Evaluating MSI using exome-sequencing data.
Figure 2: The landscape of MSI across TCGA exomes.
Figure 3: Cancer-specific signatures of MSI.
Figure 4: Signatures of MSI in MSI-H tumors.
Figure 5: Global MSI load and patient survival.

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Change history

  • 19 July 2017

    In the version of this article initially published, in Figure 4d, the column labels UCED and STAD were inadvertently switched. The error has been corrected in the HTML and PDF versions of the article.

  • 28 December 2017

    In the version of this article initially published, the numbers on the y-axis of Figure 2b were incorrect by a power of 10, and the numbers in the text describing the frequency of MSI-H tumors were also incorrect. The original text read: "Still lower, but detectable, frequencies of MSI-H were observed in 12 other cancer types; collectively, one or more individual MSI-H tumors were identified in 16 of the 18 cancer types examined". This has been corrected to: "Still lower, but detectable, frequencies of MSI-H were observed in 10 other cancer types; collectively, one or more individual MSI-H tumors were identified in 14 of the 18 cancer types examined". These errors do not impact the findings or conclusions of this work; however, they have been corrected for accuracy. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A. McKenna and other members of S.J.S. and J.S.'s laboratories for helpful advice and assistance. This work was supported in part by the Damon Runyon Cancer Research Foundation (DRG-2224-15 to R.J.H.), a Congressionally Directed Medical Research Program (PC131820 to C.C.P.), and a Young Investigator Award from the Prostate Cancer Foundation (to C.C.P.).

Author information

Authors and Affiliations

Authors

Contributions

R.J.H. and S.J.S. conceived the work and designed and performed the analyses; R.J.H., S.J.S., C.C.P., and J.S. interpreted results; and R.J.H. and S.J.S. wrote the paper with input from C.C.P. and J.S.

Corresponding authors

Correspondence to Jay Shendure or Stephen J Salipante.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Tables 2–4, 6 and 7 (PDF 1965 kb)

Supplementary Table 1

Microsatellite loci BED file (TXT 23985 kb)

Supplementary Table 5

Sample information. (XLSX 510 kb)

Supplementary Table 8

Cancer-specific locus instability portions. (TXT 14229 kb)

Supplementary Table 9

Global cluster enrichment results. (XLSX 62 kb)

Supplementary Table 10

MSI-H cancer-specific instability loci. (XLSX 326 kb)

Supplementary Table 11

Full list of unstable loci associated with global MSI. (TXT 14317 kb)

Supplementary Table 12

Literature review of top unstable loci associated with global MSI. (XLSX 63 kb)

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Hause, R., Pritchard, C., Shendure, J. et al. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 22, 1342–1350 (2016). https://doi.org/10.1038/nm.4191

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