Introduction: Glioblastoma (GBM) acquires genetic deletions that are considered critical for tumor development, presumably because these deletions result in the loss of critical tumor suppressor genes. The distinction between these functionally relevant genes and bystanders within the same loci is difficult, since oftentimes a single deletion includes many genes. Chromosome 10q deletion, the most common found in GBM, includes the tumor suppressor gene PTEN, which is well known to play an important role in development of GBM. However, several groups have proposed that the loss of other tumor suppressor genes, in addition to PTEN, may also contribute to the functional significance of chromosome 10q deletion in GBM.
Methods: We have performed comparative genomic hybridization of a retrovirus-induced mouse model of GBM in which PTEN was experimentally deleted by Cre-recombinase, in combination with PDGF overexpression, as tumor initiating alterations. A cross-species comparison was done to human GBM.
Results: The resulting mouse tumors consistently developed a series of deletions that included genes that map to human chromosome 10q, and are found among the most common genetic deletions seen in human GBM. Interestingly, these genes are found in multiple independent deletions localized in three different mouse chromosomes, suggesting that there is independent selective pressure for deletion of these different genetic loci. Furthermore, the mouse tumors did not suffer frequent copy number alterations within the chromosomal region that contains PTEN, consistent with the fact that this gene was experimentally inactivated by Cre-mediated deletion during tumor induction. The mouse tumor model that we use recapitulates the phenotype of proneural GBM, and interestingly, we found chromosome 10 deletion to provide a significant worse survival within this subgroup of patients.
Conclusions: In addition to PTEN, other genes found on chromosome 10q deletion might be independently selected for during development of GBM, as evidenced by cross-species comparison of GBM genetic alterations.
Patient Care: Identification of novel tumor suppressor genes is key for developing effective treatments and understanding mechanisms of resistance on recurrent malignant gliomas
Learning Objectives: Identification of putative tumor suppressor genes in chromosome 10q deletion