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MD Anderson Study Shows Differential RNA Editing in Cancer Cells

NEW YORK (GenomeWeb) – Cancer cells show different patterns of post-transcriptional RNA editing compared to normal cells, a new study shows, and the changes could be developed into biomarkers and potentially offer druggable targets.

Led by Leng Han, Lixia Diao, Gordon Mills, and Han Liang of MD Anderson Cancer Center, the scientists published a study today in Cancer Cell detailing the clinical relevance of adenosine to inosine (A-to-I) RNA editing in human cancers.

The study looked at A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas. The authors wrote that the study revealed "a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues."

"Previous studies have focused on DNA mutations and mainly focused on RNA editing in normal tissues. The role of RNA editing in human cancers is only beginning to emerge from those early studies of individual patient samples in a few cancer types," Liang said in a statement. "If a protein is only highly edited in the tumor proteins, but not in normal proteins, then it's possible that a specific drug could be designed to inhibit the edited mutant protein."

RNA editing after transcription is a widespread mechanism but can result in missense codon changes, modification of regulatory RNAs, and modulation of alternative splicing. A-to-I editing is the most common type found in humans, with over 1 million sites found in the genome, largely in non-coding regions.

The study suggested to the authors that clinically relevant RNA editing sites also tend to be in non-coding regions. Some were specific, though, and could be exploited. Editing events for transcripts of the genes COG3 and GRIA2 increased sensitivity to some targeted agents, while editing in AZIN1 led to decreased sensitivity. Furthermore, if the editing leads to gain or loss of function, it could either increase or decrease the sensitivity to a specific drug.

"Thus, some RNA-editing events may be functionally equivalent to 'driver' mutations, making a notable contribution to tumor initiation and growth as well as playing a critical role in response to cancer therapy," the authors wrote.

But determining clinical significance of editing events isn't without its challenges. For a large number of RNA editing sites, their overall gene expression levels also showed correlation with cancer, potentially confounding the determination of clinical relevance.

The authors called for further characterization of RNA editing, suggesting it could help scientists investigate cancer mechanisms, discover biomarkers, and inform treatments.