Characterizing DNA methylation alterations from The Cancer Genome Atlas

Abstract

The Cancer Genome Atlas (TCGA) Research Network is an ambitious multi-institutional consortium effort aimed at characterizing sequence, copy number, gene (mRNA) expression, microRNA expression, and DNA methylation alterations in 30 cancer types. TCGA data have become an extraordinary resource for basic, translational, and clinical researchers and have the potential to shape cancer diagnostic and treatment strategies. DNA methylation changes are integral to all aspects of cancer genomics and have been shown to have important associations with gene expression, sequence, and copy number changes. This Review highlights the knowledge gained from DNA methylation alterations in human cancers from TCGA.

Figure 1. CIMP in human cancer.

Eight individual methylomes are listed (numbered 1–8). Each row indicates an individual cancer methylome, in which clusters indicate individual CpG islands. CIMP-specific DNA hypermethylation is specific only for a proportion of tumors, while cancer-associated CpG islands are frequently methylated in both CIMP and non-CIMP tumors.

Figure 2. DNA demethylation dynamics in human cancers.

(A) Role of IDH1 in shaping the cancer methylome. WT IDH1 converts isocitrate to α-KG, but the mutant IDH1^R132H enzyme catalyzes the conversion α-KG to 2-HG, which inhibits TET-mediated DNA demethylation. This mechanism is proposed to explain DNA hypermethylation in IDH1- and TET-mutated cancers. (B) Proposed mechanism of DNA demethylation by the TET family of DNA demethylases, followed by thymine-DNA glycosylase (TDG) base excision repair, resulting in unmethylated cytosines.