Transposable elements drive widespread expression of oncogenes in human cancers

Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences 1 – 3 . Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence oncogenesis in a process termed onco-exaptation 4 . However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Here, we analyzed 7,769 tumors and 625 normal datasets from 15 cancer types, identifying 129 TE cryptic promoter-activation events involving 106 oncogenes across 3,864 tumors. Furthermore, we interrogated the AluJb-LIN28B candidate: the genetic deletion of the TE eliminated oncogene expression, while dynamic DNA methylation modulated promoter activity, illustrating the necessity and sufficiency of a TE for oncogene activation. Collectively, our results characterize the global profile of TE onco-exaptation and highlight this prevalent phenomenon as an important mechanism for promiscuous oncogene activation and ultimately tumorigenesis. A pan-cancer analysis identifies 129 transposable-element-driven promoter-activation events involving 106 oncogenes. At the AluJb-LIN28B locus, deletion of the transposable element eliminates oncogene expression.