Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging

doi:10.1073/pnas.0402716101

Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging

^*Department of Genetics and Pathology, The Rudbeck Laboratory, University Hospital, SE-751 85 Uppsala, Sweden; and ^†Amersham Biosciences, Box 605, SE-751 25 Uppsala, Sweden

Edited by Carlo M. Croce, Thomas Jefferson University, Philadelphia, PA, and approved June 15, 2004 (received for review April 16, 2004)

Abstract

Murine retroviruses may cause malignant tumors in mice by insertional mutagenesis of host genes. The use of retroviral tagging as a means of identifying cancer-causing genes has, however, almost entirely been restricted to hematopoietic tumors. The aim of this study was to develop a system allowing for the retroviral tagging of candidate genes in malignant brain tumors. Mouse gliomas were induced by a recombinant Moloney murine leukemia virus encoding platelet-derived growth factor (PDGF) B-chain. The underlying idea was that tumors evolve through a combination of PDGF-mediated autocrine growth stimulation and insertional mutagenesis of genes that cooperate with PDGF in gliomagenesis. Common insertion sites (loci that were tagged in more than one tumor) were identified by cloning and sequencing retroviral flanking segments, followed by blast searches of mouse genome databases. A number of candidate brain tumor loci (Btls) were identified. Several of these Btls correspond to known tumor-causing genes; these findings strongly support the underlying idea of our experimental approach. Other Btls harbor genes with a hitherto unproven role in transformation or oncogenesis. Our findings indicate that retroviral tagging with a growth factor-encoding virus may be a powerful means of identifying candidate tumor-causing genes in nonhematopoietic tumors.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: bengt.westermark{at}genpat.uu.se.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: MMLV, Moloney murine leukemia virus; PDGF, platelet-derived growth factor; PDGFB, PDGF B-chain; IPCR, inverse PCR; CIS, common integration site; NFI, nuclear factor I.