Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas. Issue 1 (23rd June 2022)

• Record Type: Journal Article
• Authors: Weishaupt, Holger; Čančer, Matko; Rosén, Gabriela; Holmberg, Karl O; Häggqvist, Susana; Bunikis, Ignas; Jiang, Yiwen; Sreedharan, Smitha; Gyllensten, Ulf; Becher, Oren J; Uhrbom, Lene; Ameur, Adam; Swartling, Fredrik J
• Is Part Of: Neuro-oncology. Volume 25:Issue 1(2023)
• Page Start: 97
• Page End: 107
• Publication Date: 2022-06-23
• Subjects: forward genetics screen -- glioblastoma -- liprin-beta-1 -- PDGFB -- RCAS; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac158
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Malignant gliomas, the most common malignant brain tumors in adults, represent a heterogeneous group of diseases with poor prognosis. Retroviruses can cause permanent genetic alterations that modify genes close to the viral integration site. Methods: Here we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next-generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies. Results: A large fraction of common integration sites contained genes that have been dysregulated or misexpressed in glioma. Others overlapped with loci identified in previous glioma-related forward genetic screens, but several novel putative cancer-causing genes were also found. Integrating retroviral tagging and clinical data, Ppfibp1 was highlighted as a frequently tagged novel glioma-causing gene. Retroviral integrations into the locus resulted in Ppfibp1 upregulation, and Ppfibp1 -tagged cells generated tumors with shorter latency on orthotopic transplantation. In human gliomas, increased PPFIBP1 expression was significantly linked to poor prognosis and PDGF treatment resistance. Conclusions: Altogether, the current study has demonstrated a novel approach to tagging glioma genes via forward genetics, validating previous results, and identifying PPFIBP1 as a putative oncogene in gliomagenesis.