Strict retroelement regulation is frequently lost following cancer transformation and generates a promising reservoir of cancer biomarkers.

Background: Retroelements are repetitive sequences that comprise 42% of the human genome and are strictly regulated through various epigenetic mechanisms. Examining retroelement expression on a locus-specific level in relation to cancer can uncover distinct disease signatures.

Results: Using over 5000 RNA-sequencing samples, we assessed retroelement transcription across 23 tissue systems, 159 cell types, 1019 cancer cell lines, and cells isolated from various stages of embryogenesis using the specialized software tool, Telescope. In healthy individuals, 11,388 retroelements were found to be actively transcribed and dynamically regulated in a tissue- and cell type-dependent manner. Using the adult human body as a reference, we observed that 94% of cancer cell lines displayed elevated transcription of at least one cancer-specific retroelement, providing a three-fold larger reservoir of cancer biomarkers (1182) than our comparable analysis of annotated protein-coding genes (338). The precise retroelements that were transcribed following tumorigenesis were influenced by the originating location, with cancers of the blood, lungs, and soft tissue displaying the highest origin-specific activation. Moreover, nearly half of the cancer-specific retroelement loci, mostly from the HERV-H family, were found to be expressed during early embryonic development.

Conclusions: Our data demonstrate that elevated transcription of certain tissue-specific and embryonic retroelements can be considered as a hallmark of tumorigenesis.