Abstract 4888: Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors
- Abstract:
- Abstract Genomic rearrangements are a hallmark of childhood solid tumors, but their mutational causes remain poorly understood. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an enzymatically active human DNA transposase expressed in the majority of rhabdoid tumors, a lethal childhood cancer. Using assembly-based whole-genome DNA sequencing, we observed previously unknown somatic genomic rearrangements in primary human rhabdoid tumors. These rearrangements were characterized by deletions and inversions involving PGBD5-specific signal (PSS) sequences at their breakpoints, with some recurrently targeting tumor suppressor genes, leading to their inactivation. PGBD5 was found to be physically associated with human genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. We found that ectopic expression of PGBD5 in primary human cells was sufficient to promote penetrant cell transformation in vitro and in immunodeficient mice in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain, as well as end-joining DNA repair, and induced distinct structural rearrangements, involving PSS-associated breakpoints, similar to those found in primary human rhabdoid tumors. Thus, PGBD5 defines a distinct class of oncogenic mutators and induces site-specific somatic DNA rearrangements in human cancer. Citation Format: Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis. Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4888. doi:10.1158/1538-7445.AM2017-4888
- Authors:
- AG Henssen, R Koche, J Zhuang, E Jiang, C Reed, A Eisenberg, E Still, E Rodríguez-Fos, S Gonzalez, M Puiggròs, AN Blackford, CE Mason, ED Stanchina, M Gönen, A-K Emde, M Shah, K Arora, C Reeves, ND Socci, E Perlman, CR Antonescu, CW Roberts, H Steen, E Mullen, SP Jackson, D Torrents, Z Weng, SA Armstrong, A Kentsis
- Journal:
- Cancer Research
- Citation info:
- 77(13_Supplement):4888-4888
- Publication date:
- 1st Jul 2017
- Full text
- DOI