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.
Highlights
More than 50% of the human genome sequence is derived from transposable element (TE) insertions (Lander et al, 2001; de Koning et al, 2011)
This is true for Alu elements, many of which are found in the introns of human genes and transcribed as read-through transcripts initiated from RNA Pol II gene promoters (Deininger, 2011)
Our confidence in the ability to measure L1-initiated transcripts is higher owing to the focus on previously identified full-length, intact elements that are located in intergenic regions
Summary
More than 50% of the human genome sequence is derived from transposable element (TE) insertions (Lander et al, 2001; de Koning et al, 2011). The vast majority of TE-derived sequences in the human genome correspond to relatively ancient insertions that are no longer capable of transposition (Mills et al, 2007). Alu and SVA SINEs are non-autonomous TEs that are mobilized via the transpositional machinery encoded by the autonomous L1 family of LINEs. Recent evidence indicates that a handful of HERV-K endogenous retroviral elements remain active in the human genome (Wildschutte et al, 2016)
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