Pinpointing novel molecular and cellular functions generated by retroelement onco-exaptation

Exaptation, the co-option of endogenous retroelements (EREs) for new molecular and cellular functions that confer a host fitness advantage, is a major force in evolution, but may also be exploited, through onco-exaptation, by tumour cells to promote the oncogenic process. There are over 4 million well-recognised and annotated individual ERE integrations in the human genome.

However, their participation at the level of the more complex transcriptome is far less well understood and, therefore, the number of onco-exaptation events is likely vastly underestimated. To allow detection and quantitation of ERE transcription, we have recently de novo assembled the cancer transcriptome.

This resulted in a doubling of the known transcriptome, particularly of unannotated or partially annotated transcripts derived from or overlapping with EREs.

Here, we propose to utilise this extended view of ERE transcription as the framework for:•building a genome-wide map of functionally validated ERE onco-exaptation events and •pinpointing novel, targetable functions of EREs in immunity, cancer and their intersectionAlthough we identified thousands of novel ERE-overlapping transcripts in cancer, the majority are likely the consequence of transcriptional activation of normally silent EREs, with little or no impact on host cell function.

Impactful and inconsequential ERE integrations will be distinguished based on a number of features, including association with cancer overall survival or response to immunotherapy, impact on adjacent gene function, evolutionary conservation and functional domain and folding predictions.

Postulated function will ultimately be tested extensively in in vitro cancer cell lines, ex vivo cancer patient material and in vivo mouse cancer models, tailored to the relevant onco-exaptation event.

The modification of existing gene function or the creation of new function by ERE onco-exaptation will undoubtedly uncover new targets and opportunities for cancer treatment.