RNA Editors and DNA Mutators: Cancer Heterogeneity Through Sequence Diversification

Abstract

Cancer development and progression is strongly associated with somatic mutations. From oncogenic hits that initiate the primary tumor formation to metastasis, the tumor mutational burden (TMB) plays a prominent role in the disease progression for the vast majority of cancer types. Not only are heterogeneous mutational loads or genetic heterogeneity causal to transcriptomic and proteomic discrepancies and to phenotypic diversity between individuals, they are also between tumor cells. But in addition to mutations, a new set of alterations at the level of RNA (termed "epitranscriptomic") can also cause informational heterogeneity. Chief among epitranscriptomic modifiers are the RNA editing enzymes (ADAR and AID/APOBEC family deaminases), which catalyze A-to-I and C-to-U base changes within RNA transcripts. Because all of these enzymes also retain the ability to mutate DNA, they can be generally considered as central drivers of inter-tumor heterogeneity either at the DNA level or at the RNA level. Here, we connect genome/transcriptome diversification with tumorigenesis and suggest specific roles for these DNA/RNA deaminases in the context of tumorigenesis both through genome level events (mutations) and through transcriptome level events as these converge into a common sequence diversification strategy.