Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas.

Weishaupt H, Čančer M, Rosén G, Holmberg KO, Häggqvist S, Bunikis I, Jiang Y, Sreedharan S, Gyllensten U, Becher OJ, Uhrbom L, Ameur A, Swartling FJ

Neuro-oncology 25 (1) 97-107 [2023-01-05; online 2022-06-24]

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. 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. 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. 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.

Bioinformatics Support for Computational Resources [Service]

NGI Short read [Collaborative]

NGI Uppsala (Uppsala Genome Center) [Collaborative]

National Genomics Infrastructure [Collaborative]

PubMed 35738865

DOI 10.1093/neuonc/noac158

Crossref 10.1093/neuonc/noac158

pmc: PMC9825320
pii: 6615415

Publications 9.5.0