Tumor Epigenetics

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Science  19 Jul 2013:
Vol. 341, Issue 6143, pp. 216
DOI: 10.1126/science.341.6143.216-c

That human tumors display both genetic mutations and epigenetic alterations—for example, in DNA methylation—has been known for many years; with the completion of cancer genome sequencing projects, possible causal links between the two have come into sharper focus. The discovery of recurrent tumor-associated mutations in genes that encode chromatin-modifying enzymes or DNA methyltransferases represents a clear link between tumor genotype and “epigenotype.” Emerging evidence suggests that a link can be subtle, as illustrated by two studies describing consistent epigenetic alterations in tumors with mutations in the gene encoding the metabolic enzyme succinate dehydrogenase (SDH). Killian et al. find that gastrointestinal stromal tumors harboring SDH mutations are characterized by dramatic and widespread DNA hypermethylation, whereas Letouzé et al. report that SDH-mutant paragangliomas display DNA hypermethylation that is associated with the silencing of genes involved in neuroendocrine cell differentiation. Both groups hypothesize that the hypermethylation phenotype is due to the aberrant accumulation of an oncometabolite that inhibits DNA-demethylating enzymes, with succinate being a strong candidate.

Cancer Discov. 3, 648 (2013); Cancer Cell 23, 739 (2013).

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