Transposable elements drive widespread expression of oncogenes in human cancers

Abstract

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.

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

“…Strong demonstrations of such adaptive roles are scarce. Notably, the Wang lab recently showed that an AluJb element acts as an oncogenic promoter to drive LIN28B expression and tumour progression in lung cancer (Jang et al, 2019). In our study we identified an LTR2 element, the genetic and epigenetic perturbation of Figure 7A,B).…”

“…It had been previously postulated that the epigenetically relaxed state of cancer cells provides a window of opportunity for ERV activation, triggering their intrinsic regulatory capacity Chuong et al, 2017;Lamprecht et al, 2010). However, to the best of our knowledge, all examples to date supporting this hypothesis have involved activation of cryptic promoters to drive expression of adjacent genes Jang et al, 2019). Whilst we uncovered some examples of chimeric transcripts starting from ERVs in AML (e.g., LTR2C-SAGE1), which are not present in differentiated myeloid cells, our analyses suggest that active A-DARs mainly harbour chromatin signatures of enhancers.…”

“…Various studies have documented widespread epigenetic and transcriptional deregulation of TEs in several cancer types, raising the possibility that TE-derived regulatory elements may be exploited to promote tumorigenesis Burns, 2017). Indeed, activation of LTR-based promoters initiates cancerspecific chimeric transcripts in Hodgkin lymphoma, melanoma and diffuse large B-cell lymphoma, among others Edginton-White et al, 2019;Jang et al, 2019). These so-called onco-exaptation events were recently shown to be highly prevalent in multiple cancer types (Jang et al, 2019).…”

“…Indeed, activation of LTR-based promoters initiates cancerspecific chimeric transcripts in Hodgkin lymphoma, melanoma and diffuse large B-cell lymphoma, among others Edginton-White et al, 2019;Jang et al, 2019). These so-called onco-exaptation events were recently shown to be highly prevalent in multiple cancer types (Jang et al, 2019). However, studies to date have been largely centered on LTR promoter activity.…”

Mobile Element Insertions and Associated Structural Variants in Longitudinal Breast Cancer Samples

“…Previous work has shown that changes in mobile element methylation and expression can impact nearby gene expression (Xie et al 2013;Jang et al 2019). This shows that mobile elements, even at the locus level, can change expression throughout cancer progression, potentially altering the expression of one or several genes, or changing which mobile elements are capable of retrotransposition.…”