Patterns of Transposable Element Expression and Insertion in Cancer

Abstract

Human transposable element (TE) activity in somatic tissues causes mutations that can contribute to tumorigenesis. Indeed, TE insertion mutations have been implicated in the etiology of a number of different cancer types. Nevertheless, the full extent of somatic TE activity, along with its relationship to tumorigenesis, have yet to be fully explored. Recent developments in bioinformatics software make it possible to analyze TE expression levels and TE insertional activity directly from transcriptome (RNA-seq) and whole genome (DNA-seq) next-generation sequence data. We applied these new sequence analysis techniques to matched normal and primary tumor patient samples from the Cancer Genome Atlas (TCGA) in order to analyze the patterns of TE expression and insertion for three cancer types: breast invasive carcinoma, head and neck squamous cell carcinoma, and lung adenocarcinoma. Our analysis focused on the three most abundant families of active human TEs: Alu, SVA, and L1. We found evidence for high levels of somatic TE activity for these three families in normal and cancer samples across diverse tissue types. Abundant transcripts for all three TE families were detected in both normal and cancer tissues along with an average of ~80 unique TE insertions per individual patient/tissue. We observed an increase in L1 transcript expression and L1 insertional activity in primary tumor samples for all three cancer types. Tumor-specific TE insertions are enriched for private mutations, consistent with a potentially causal role in tumorigenesis. We used genome feature analysis to investigate two specific cases of putative cancer-causing TE mutations in further detail. An Alu insertion in an upstream enhancer of the CBL tumor suppressor gene is associated with down-regulation of the gene in a single breast cancer patient, and an L1 insertion in the first exon of the BAALC gene also disrupts its expression in head and neck squamous cell carcinoma. Our results are consistent with widespread somatic activity of human TEs leading to numerous insertion mutations that can contribute to tumorigenesis in a variety of tissues.

Peer Review #2 of "Biomarker potential of repetitive-element transcriptome in lung cancer (v0.2)"

“…show minimal differential expression (Supplemental Tables S3 and S6), indicating that RE expression change should not be related to families but particular REs. It further supports the established proposal that RE expression seems to be strictly controlled before and after any oncogenic transformation (Gibb et al, 2015;Clayton et al, 2016;Lättekivi et al, 2018;Arroyo et al, 2018) and cannot be explained by a broad deregulation as initially proposed by Shalgi et al (Shalgi et al, 2010).…”

“…Some REs can contain regulatory sequences (acting as promoters and transcription signals) that enable them to dysregulate adjacent genes and drive to, for example, cancer (Pavlicev et al, 2015;Trizzino et al, 2018;Jang et al, 2019). A body of evidence is accumulating against the non-specific dysregulation of RE and favouring the concept of a fine-tuned change of expression after an oncogenic process (Gibb et al, 2015;Clayton et al, 2016;Larrosa et al, 2018). That could explain why 'read-through' transcription of intronic transposons and interspersed repeats occurs, and why this expression is tissue-or disease-specific (Gnanakkan et al, 2013).…”

Transposable Element Exprssion in Tumors is Associated with Immune Infiltration and Increased Antigenicity

“…S4G), one possible explanation for the observed extensive positive correlations in KIRC is that TEs may be a significant contributor to DDR. Somatic TE transposition events have been previously described in TCGA samples to lead to insertional mutations private to tumors (35) and retrotransposition is known to create DNA double-strand breaks (36). KIRC was recently observed to harbor the highest proportion of insertion-and-deletion tumor mutations compared to other TCGA cancer types (37).…”

Human Retrotransposon Insertion Polymorphisms Are Associated with Health and Disease via Gene Regulatory Phenotypes

“…Nevertheless, the joint phenotypic implications of retrotransposon generated human genetic variation, coupled with their capacity for genome regulation, have yet to be fully explored. We previously studied the implications of somatic retrotransposition for the etiology of cancer vis a vis retrotransposon induced regulatory changes in tumor suppressor genes ( Clayton et al, 2016 ). For the current study, we were curious to understand how insertion polymorphisms generated by human retrotransposon activity may be related to commonly expressed health and disease phenotypes.…”