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PGBD5 promotes site-specific oncogenic mutations in human tumors.

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.

SUBMITTER: Henssen AG

PROVIDER: S-EPMC5489359 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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PGBD5 promotes site-specific oncogenic mutations in human tumors.

Henssen Anton G AG Koche Richard R Zhuang Jiali J Jiang Eileen E Reed Casie C Eisenberg Amy A Still Eric E MacArthur Ian C IC Rodríguez-Fos Elias E Gonzalez Santiago S Puiggròs Montserrat M Blackford Andrew N AN Mason Christopher E CE de Stanchina Elisa E Gönen Mithat M Emde Anne-Katrin AK Shah Minita M Arora Kanika K Reeves Catherine C Socci Nicholas D ND Perlman Elizabeth E Antonescu Cristina R CR Roberts Charles W M CWM Steen Hanno H Mullen Elizabeth E Jackson Stephen P SP Torrents David D Weng Zhiping Z Armstrong Scott A SA Kentsis Alex A

Nature genetics 20170515 7

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 inactivate ...[more]

PMID: 28504702

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Project description:BackgroundEmerging studies support the oncogenic role of WD repeat domain 62 (WDR62) in few tumors, while no pan-cancer analysis is available. In this study, we analyzed systematically the oncogenic role of WDR62 across a series of human tumors based on bioinformatic data mining.MethodsThe expression level of WDR62 was analyzed via GEPIA2, TIMER, UALCAN, and StarBase databases. The prognostic role was analyzed via GEPIA2, TIMER, UALCAN, StarBase, TISIDB, TCGA portal, Kaplan-Meier Plotter, and PrognoScan databases. Then, we explored the causes for WDR62 abnormal expression via TCGA portal and UALCAN databases. Subsequently, the STRING and GeneMANIA databases were used to find the interactive networks for WDR62. Furthermore, we analyzed the correlation between WDR62 expression and immune features via TIMER and TISIDB databases.ResultsWe found that WDR62 was significantly upregulated in most of the tumors and correlated with poor prognosis mainly in 6 candidate tumors-BLCA, BRCA, KIRC, KIRP, LIHC, and LUAD. Abnormal WDR62 expression may be probably attributed to TP53 mutation and promoter DNA methylation. Relative network analysis demonstrated that WDR62 was mainly involved in MAPK and toll-like receptor signaling pathway. WDR62 expression was associated with various immune cell infiltrations, especially cancer-associated fibroblasts (CAF) and T cell regulatory (Treg) cells, and was markedly correlated with poor prognosis. Moreover, WDR62 expression was closely associated with the expression of some immunomodulators such as PD-L1 and has a significant prognostic value.ConclusionsOur study revealed that WDR62 could serve as a diagnostic and prognostic biomarker for several cancers. Importantly, WDR62 was closely associated with various immune cell infiltration, and to a certain extent, it can predict the effect of immunotherapy in particular PD1/PD-L1 inhibitors. Our pan-cancer study provided useful information on the oncogenic role of WDR62, contributing to further exploring the underlying mechanisms.

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PGBD5 promotes site-specific oncogenic mutations in human tumors.

Publications

PGBD5 promotes site-specific oncogenic mutations in human tumors.

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