Abstract 1103: Human tumorigenesis induced by endogenous DNA transposase

Recent cancer genome surveys have revealed extremely low rates of coding gene mutations in distinct tumor subtypes, suggesting that alternative mechanisms must contribute to their pathogenesis. Transposons are mobile genetic elements that are found in all living organisms, including humans where they occupy nearly half of the genome. Their mobilization can cause structural rearrangements in normal and cancer cells. However, it remains unknown whether transposition is a cause of cellular transformation or merely a bystander effect of dysregulated gene expression. Here, we report that PGBD5, a recently characterized human gene related to the piggyBac transposase from the cabbage looper moth, is aberrantly expressed in rhabdoid tumors, medulloblastoma, acute leukemias, and some sarcomas and carcinomas. Ectopic expression of PGBD5 in non-transformed primary human cells is sufficient to induce anchorage independence in vitro and penetrant tumor formation in immunodeficient mice in vivo. PGBD5 expression is sufficient to induce genomic mobilization of engineered DNA transposons in human cells, and purified recombinant PGBD5 exhibits transposase domain-dependent endonuclease activity in vitro. Flanking-sequence exponential anchored PCR and massively parallel sequencing of DNA transposon integrations revealed distinct activity on piggyBac-like inverted terminal repeats, and preference for specific euchromatic human genomic loci. This enables mapping of structural rearrangements of endogenous human transposable elements in primary human tumor genomes, some of which target genes involved in cellular transformation. We find that PGBD5 transposase-induced cell transformation is associated with morphologic de-differentiation, induction of distinct Polycomb gene expression programs and structural chromatin remodeling, consistent with its epigenetic control. These findings reveal an unanticipated mechanism of human tumorigenesis, genomic plasticity and structural alterations of non-coding regulatory genomic loci in human cancer. Citation Format: Anton Henssen, Amy Eisenberg, Eileen Jiang, Elizabeth Henaff, Richard Koche, Melissa Burns, Julianne R. Carson, Gouri Nanjangud, Eric Still, Jorge Gandara, Paolo Cifani, Avantika Dhabaria, Xiaodong Huang, Elisa de Stanchina, Elizabeth Mullen, Hanno Steen, Elizabeth Perlman, Jeffrey Dome, Cristina Antonescu, Cedric Feschotte, Christopher E. Mason, Alex Kentsis. Human tumorigenesis induced by endogenous DNA transposase. [abstract].