Abstract

CpG dinucleotides are the main mutational hot-spot in most cancers. The characteristic elevated C>T mutation rate in CpG sites has been related to 5-methylcytosine (5mC), an epigenetically modified base which resides in CpGs and plays a role in transcription silencing. In brain nearly a third of 5mCs have recently been found to exist in the form of 5-hydroxymethylcytosine (5hmC), yet the effect of 5hmC on mutational processes is still poorly understood. Here we show that 5hmC is associated with an up to 53% decrease in the frequency of C>T mutations in a CpG context compared to 5mC. Tissue specific 5hmC patterns in brain, kidney and blood correlate with lower regional CpG>T mutation frequency in cancers originating in the respective tissues. Together our data reveal global and opposing effects of the two most common cytosine modifications on the frequency of cancer causing somatic mutations in different cell types.

Article and author information

Author details

  1. Marketa Tomkova

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Michael McClellan

    Ludwig Cancer Research Oxford, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Skirmantas Kriaucionis

    Ludwig Cancer Research Oxford, University of Oxford, Oxford, United Kingdom
    For correspondence
    skirmantas.kriaucionis@ludwig.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  4. Benjamin Schuster-Boeckler

    Ludwig Cancer Research Oxford, University of Oxford, Oxford, United Kingdom
    For correspondence
    benjamin.schuster-boeckler@ludwig.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Daniel Zilberman, University of California, Berkeley, United States

Version history

  1. Received: April 20, 2016
  2. Accepted: May 13, 2016
  3. Accepted Manuscript published: May 16, 2016 (version 1)
  4. Accepted Manuscript updated: May 17, 2016 (version 2)
  5. Accepted Manuscript updated: May 17, 2016 (version 3)
  6. Version of Record published: July 4, 2016 (version 4)

Copyright

© 2016, Tomkova et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,076
    views
  • 719
    downloads
  • 28
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Marketa Tomkova
  2. Michael McClellan
  3. Skirmantas Kriaucionis
  4. Benjamin Schuster-Boeckler
(2016)
5-hydroxymethylcytosine marks regions with reduced mutation frequency in human DNA
eLife 5:e17082.
https://doi.org/10.7554/eLife.17082

Share this article

https://doi.org/10.7554/eLife.17082

Further reading

    1. Cancer Biology
    2. Genetics and Genomics
    Jose Mario Bello Pineda, Robert K Bradley
    Research Article

    Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10–50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

    1. Cancer Biology
    2. Cell Biology
    Helmut Bischof, Selina Maier ... Robert Lukowski
    Research Article

    Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the ‘Warburg effect’, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.