Chromatin organization is a major influence on regional mutation rates in human cancer cells

Abstract

Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells1,2,3,4,5,6,7. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

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Figure 1: The density of somatic mutations in cancer genomes correlates with H3K9me3 modification levels and anti-correlates with genomic features associated with open chromatin.
Figure 2
Figure 3: Chromatin organization predicts cancer genome mutation density for diverse mutation types and sequence contexts.
Figure 4: Prediction of cancer SNV density variation using integrated models.

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Acknowledgements

This work was funded by an European Research Council (ERC) Starting Grant, European Union Framework 7 project 277899 4DCellFate, ERASysBioPLUS, Ministerio de Ciencia e Innovación (MICINN) grants BFU2008-00365 and BFU2011-26206, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), the European Molecular Biology Organization (EMBO) Young Investigator Program, the EMBL-CRG Systems Biology Program and a Juan de la Cierva postdoctoral fellowship to B.S-B. We thank T. Vavouri and T. Warnecke for comments on the manuscript, and R.S. Hansen for assistance with analysing replication timing data.

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B.S.-B. performed all analyses. B.S.-B. and B.L. designed analyses and wrote the manuscript. B.L. conceived the study.

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Correspondence to Ben Lehner.

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The authors declare no competing financial interests.

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Schuster-Böckler, B., Lehner, B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488, 504–507 (2012). https://doi.org/10.1038/nature11273

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