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Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer

Key Points

  • Tumour genomes are characterized by extensive alterations that affect the genome as well as the epigenome. Both types of alterations change global gene expression patterns.

  • Novel genome-wide sequencing technologies allow the comprehensive search for genetic and epigenetic alterations. These technologies provide extensive data sets on genes and gene regions that are altered in a cancer genome.

  • Many malignancies show mutations or other chromosomal rearrangements in genes that are responsible for the establishment, maintenance and reading of epigenetic patterns.

  • Epigenetic pathways include DNA methylation, histone modifications and chromatin remodelling.

  • Many tumour genomes carry a specific mutation in a regulator of the epigenome (such as histone H3.3 K27M and isocitrate dehydrogenase 1 (IDH1) R132H mutations) and are characterized by subgroup-specific DNA and histone modification patterns. This suggests that mutations in regulators of the epigenome are mechanistically linked to the altered epigenome.

  • In this Review, we propose a systematic integrative analysis of profiling data to uncover molecular mechanisms that lead to altered epigenomes.

  • Mutations in regulators of the epigenome are attractive targets for epigenetic therapy.

Abstract

Malignancies are characterized by extensive global reprogramming of epigenetic patterns, including gains or losses in DNA methylation and changes to histone marks. Furthermore, high-resolution genome-sequencing efforts have discovered a wealth of mutations in genes encoding epigenetic regulators that have roles as 'writers', 'readers' or 'editors' of DNA methylation and/or chromatin states. In this Review, we discuss how these mutations have the potential to deregulate hundreds of targeted genes genome wide. Elucidating these networks of epigenetic factors will provide mechanistic understanding of the interplay between genetic and epigenetic alterations, and will inform novel therapeutic strategies.

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Figure 1: Enzymes involved in DNA and histone modification pathways.
Figure 2: Evolution of global epigenetic data in cancer.
Figure 3: Mutations in regulators of the epigenome identified in cancer.
Figure 4: Workflow of integrative analysis for molecular profiling of cancer.

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Acknowledgements

The authors thank Y. Assenov for his support and discussions for the figure design. C.P. was supported by the Deutsche Forschungsgemeinschaft through SPP1463; C.P. and O.B. by the German Federal Ministry of Education and Research (BMBF) for the International Cancer Genome Consortium (ICGC) project 'Genomes of early onset prostate cancer'; C.P. and R.C. by the José Carreras Foundation; C.P. and A.M.L. by the German Cancer Research Center (DKFZ) and the Helmholtz Foundation; and A.M.L. by a visiting scientist fellowship from the DKFZ. This project was partially funded by grants from the German Cancer Consortium (DKTK) molecular diagnostics in paediatric malignancies to P.L. and S.M.P., and in oncogenic pathways to C.P. The PedBrain Tumor Project contributing to the ICGC was funded by the German Cancer Aid (109252) and the BMBF NGFNplus #01GS0883.

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Glossary

Epigenetic modifications

Modifications of DNA and histones that do not change the genetic code but have an effect on gene expression or chromatin condensation; these modification patterns are stably transmitted to daughter cells after cell division.

Epigenome

The entire epigenetic modifications of DNA and histones in the genome of a tissue.

CpG island methylator phenotypes

Enrichments for the methylation of GC-rich promoter sequences that were initially defined in a colon cancer study.

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Plass, C., Pfister, S., Lindroth, A. et al. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat Rev Genet 14, 765–780 (2013). https://doi.org/10.1038/nrg3554

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