A small number of impactful onco-exaptation events have been described in recent years underscoring their potential importance, but their true number is likely vastly underestimated owing to the challenges of RTE study.
RTE integrations are reasonably well recognised and annotated at the genome level. However, much less understood is their participation at the more complex transcriptome level, particularly where aberrant transcriptional patters are expected, such as in cancer. Without precise knowledge of the structure of transcripts that are initiated by or include RTEs, their transcriptional activity or any resulting protein products cannot be accurately defined. RTE-derived exons have been traditionally underrepresented in past transcriptome assembly efforts owing to exclusion of repetitive reads and loci. We therefore built a genome-guided de novo transcriptome assembly that captures the diversity of RTE transcripts. We have made use of the altered transcriptional landscape of cancer to identify RTE-overlapping transcripts that might have been harder to detect in other cellular states. This assembly doubled the number of previously annotated transcripts that include RTEs, several thousand of which were found expressed specifically in one or a few related cancer types, and captured a significant number of previously unannotated isoforms of known genes, with the potential to alter the canonical gene function or to gain novel function.
By applying a number of criteria, including evolutionary conservation, putative or known function the affected genes in cancer, predicted impact of RTE, expression pattern and correlation with clinical outcomes, we prioritised a number of possible onco-exaptation events. These are now been systematically evaluated in appropriate experimental systems. Up to this point of the project, we have characterised and reported three such events. These include the co-option of the Human Endogenous Retrovirus (HERV)-K(HML-2) envelope glycoprotein as a putative tumour-associated antigen targeted by antibodies during immunotherapy of lung adenocarcinomas, the HERV-H-driven ectopic expression of Calcium-binding protein Calbindin controlling senescence and inflammation in lung squamous cell carcinomas, and RTE-mediated reduction in the expression of several genes necessary for cellular fitness of esophageal adenocarcinomas.
