Insertional activity of human Alu and L1 retrotransposons is associated with DNA repair pathways and genome instability in cancer.

Transposable elements (TEs) are a major source of genomic variability, yet their relation with other mutational processes and DNA repair in cancers remains poorly understood. Here we combined deep sequencing approaches (RNAseq, whole exome sequencing, and targeted TE-flank sequencing) with computational analyses to investigate the transcriptional activity of active human L1 and Alu elements across 526 experimental and 2488 TCGA cancer samples. By quantifying somatic TE insertions in 40 experimental pairs of cancer and matched normal tissues, we found that TE insertional activity (roughly 20 insertions per sample for each class of TEs) correlates with L1 transcription, is increased in cancers and has substantial intersample variability. TE insertions also correlated with activation of non-homologous end joining, mismatch and nucleotide excision repair pathways, and with transcription of TERT and APOBEC3B genes. Based on highly correlated genes, we created an expression signature reflecting TE insertional activity (AUC 0.819-0.903). On larger experimental and literature tumor cohorts, the signature strongly correlated with the activation levels of most of DNA repair pathways except those leading to ATM checkpoint activation and cell cycle arrest. It was also associated with many genome instability markers (chimeric genes, tumor mutation burden, gene copy number variation, loss of heterozygosity), but showed reduced values in cancers with microsatellite instability. Finally, the signature was associated with worse overall survival in pancreatic cancer (HR 5.9) and lesser effects in stomach, lung, and cervical cancers. These results shed light on the interplay of TE activities, DNA repair, and genome instability in human cancers.