Thompson, Rachael S.; (2024) Exploring the endogenous retroelement transcriptome for epithelial cancer-specific targets and biomarkers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Retrotransposable elements (RTEs), although fragmented and mutated, contain regulatory elements able to influence the genome and transcriptome. The hypomethylated state of cancer genomes allows for RTE expression, thus revealing cancer-specific effects on the transcriptome. These effects were recently annotated through a genome-guided de novo transcriptome assembly, which is explored in this thesis to identify targets and biomarkers in epithelial cancers. The increased search space of the RTE transcriptome was used to identify known and novel breast tumour-specific transcripts, based on expression in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets, that may be present in liquid biopsies. These tissue-specific transcripts were searched for in blood derived extracellular RNAseq data, with the aim to separate breast tumour bearing donors and others, both healthy and not. Alternatively, cancer-specific plasma membrane proteins could be used to diagnose patients from tissue biopsies, and be used as therapy targets. The RTE transcriptome encodes predicted transmembrane domain containing open reading frames (ORFs) arising purely from RTEs and from gene-RTE chimeras. Although RTEs are present in the healthy genome, their derived peptides are not always tolerogenic, this combined with being less polymorphic than mutations, make RTEs a potentially rich source of universal cancer-specific antigen. In this work, candidates for in vitro stability testing were selected computationally based on their cancer specificity, possible antigenicity, and predicted transmembrane domain position. Beyond diagnosis, markers of patient survival and immunotherapy response are important for patient stratification and further elucidating disease mechanisms. In kidney renal clear cell carcinoma (KIRC), previous work had suggested several RTE loci were associated with response and give rise to tumour-associated antigens. This work explores the RTE expression landscape using an updated loci annotation in the context of KIRC-characteristic pseudohypoxia, as well as surveying the KIRC-specific RTE transcriptome for markers of survival.

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