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Cancer Epigenetics

Although cancer is typically considered a genetic disease, we are beginning to appreciate that epigenetic alterations play profound roles.


Source: Flavahan WA, Gaskell E, Bernstein BE. Science. 2017.

At least half of human cancers harbor recurrent mutations in chromatin-associated proteins. In addition, genetic mutations in metabolic enzymes have the capacity to affect the chromatin landscape indirectly. For example, IDH mutations result in global DNA methylation changes that disrupt genome topology and gene expression programs.

Accumulating evidence also suggests that epigenetic aberrations — resulting from metabolic and environmental stimuli for example — can activate oncogenes and silence tumor suppressors in the absence of genetic changes. Indeed, some cancers arise because of a single mutation to a single gene (such as Wilms tumor, a form of pediatric cancer) or appear to lack recurrent mutations altogether (such as pediatric ependymoma). Examples include:

  • Links between folate metabolism and methylase activity
  • Environmental factors that promote DNA hypermethylation in gastrointestinal tissues
  • Potential effects of microenvironmental stress on chromatin regulator expression

See Flavahan et al., 2017 for further discussion.

Because it is clear that the epigenome can be molded by environmental factors (e.g., famine, exposure to drugs during gestation), a better understanding of the epigenomic landscape — and how it is altered in disease states like cancer — can lend insight into pathologies that are not associated with particular mutations. In essence, studying epigenetics in cancer can provide a general framework for understanding how the environment can trigger disease, something DNA sequencing alone cannot reveal.

Several groups within the program work to understand epigenetic mechanisms in cancer potentiation, initiation, evolution, and resistance. Ongoing work in this area includes epigenomic mapping and single-cell transcriptomics of tumor samples. We also leverage the large-scale screening capabilities of the Broad Center for the Development of Therapeutics (CDoT) and Genetic Perturbation Platform (GPP) to explore chromatin mechanisms and dependencies of cancer cell lines.

 

Projects

  1. Chromatin and DNA methylation changes in cancer
    Ongoing large scale mapping projects include multiple myeloma and CLL.

    Landau DA, Clement K, et al. Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. Cancer Cell. 2014.

    Kottakis F, et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature. 2016.

  2. Chromatin remodeling in cancer

    Boulay G, Sandoval GJ, et al. Cancer-specific retargeting of BAF complexes by a prion-like domain Cell. 2017.

  3. Tumor heterogeneity, developmental hierarchies, and drug resistance
    We apply various single-cell RNA sequencing and epigenome mapping technologies to study tumor heterogeneity, evolution and response to therapy. Current projects include mapping single cell transcriptomes in head and neck cancer, glioblastoma, and AML, amongst others.

    We also use patient-derived cell line models and primary tumor samples to understand mechanisms of resistance acquisition. We leverage the screening capabilities of CDoT, the Cancer Cell Line Factory and the GPP, as well as other CRISPR-based technologies.

    Liau BB, Sievers C, et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell. 2017.

    Knoechel B et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet. 2014.

    Suvà ML et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 2014.

  4. Enhancer hijacking through genome rearrangements and topological alterations
    We apply epigenomic and topology mapping technologies to understand how cis regulatory elements such as enhancers and insulators are disrupted in cancer. Current projects include colon cancer, gastrointestinal stromal tumors, lymphoma, and glioblastoma, amongst others.

    Flavahan WA, Drier Y, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016.

    Drier Y, et al. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat Genet. 2016.

    Ryan RJ, et al. Detection of enhancer-associated rearrangements reveals mechanisms of oncogene dysregulation in B-cell lymphoma. Cancer Discov. 2015.