PGBD5 promotes site-specific oncogenic mutations in human tumors

Nat Genet. 2017 Jul;49(7):1005-1014. doi: 10.1038/ng.3866.

Anton G Henssen ¹, Richard Koche ², Jiali Zhuang ³, Eileen Jiang ¹, Casie Reed ¹, Amy Eisenberg ¹, Eric Still ¹, Ian C MacArthur ¹, Elias Rodríguez-Fos ⁴, Santiago Gonzalez ⁴, Montserrat Puiggròs ⁴, Andrew N Blackford ⁵, Christopher E Mason ⁶, Elisa de Stanchina ⁷, Mithat Gönen ⁸, Anne-Katrin Emde ⁹, Minita Shah ⁹, Kanika Arora ⁹, Catherine Reeves ⁹, Nicholas D Socci ¹⁰, Elizabeth Perlman ¹¹, Cristina R Antonescu ¹², Charles W M Roberts ¹³, Hanno Steen ¹⁴, Elizabeth Mullen ¹⁵, Stephen P Jackson ⁵ ¹⁶ ¹⁷, David Torrents ⁴ ¹⁸, Zhiping Weng ³, Scott A Armstrong ² ¹⁹ ²⁰, Alex Kentsis ¹ ¹⁹ ²⁰

Affiliations

1 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2 Cancer Biology &Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3 Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
4 Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center (BSC-CNS), Barcelona, Spain.
5 The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
6 Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
7 Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
8 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9 New York Genome Center, New York, New York, USA.
10 Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
11 Northwestern University Feinberg School of Medicine, Ann &Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
12 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
13 Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
14 Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
15 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
16 Department of Biochemistry, University of Cambridge, Cambridge, UK.
17 The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
18 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
19 Weill Cornell Medical College, Cornell University, New York, New York, USA.
20 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

PMID: 28504702 DOI: 10.1038/ng.3866

Abstract

Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA Sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.

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