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Periodic Reporting for period 3 - RNAEDIT (RNA EDITING IN HEALTH AND DISEASE)

Reporting period: 2017-12-01 to 2019-05-31

The main objectives are to
(a) catalog RNA editing events in the context of tumour progression and then most importantly to
(b) understand the relevance of such events to tumour development and maintenance.
Given the emerging understanding of the importance of RNA editing to disease progression and manifestations, these findings will be of fundamental importance to our understanding of diseases that are heritable but lack a clear genetic component (and by extension, to novel therapeutic approaches to countering them).
To date, we have profiled ~110 DLBCL tumours at the RNA level but also through whole genome sequencing, and have identified through comparisons between RNA and DNA, thousands of editing events that are common to individual tumours. We have validated many of these, and are now attempting to address the impact of editing on individual pathways within the cells of interest.
We have identified editing events common to individual tumours that are known to arise as mutations at the population level upon DLBCL relapse. This finding raises the distinct possibility that RNA editing (which is co-transcriptional) pre-dates DNA mutation and that the editing enzymes themselves (which are known to also target DNA albeit at lower frequencies) might be upregulated for RNA targeting purposes in the context of inflammation and tumour progression but might also become the direct catalysts for DNA mutation. This result, which we are now trying to validate, was unexpected but is of fundamental importance to cancer genesis.