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Background: Gliomas are the most common primary brain tumors and their prognosis is related to WHO histopathological grade. Glioblastoma (grade IV astrocytoma or GBM) is characterized by microscopic invasion into surrounding brain and universally poor prognosis despite treatment with surgery, radiation and chemotherapy . Recently, the matricellular protein periostin (POSTN) has been shown to be associated with increased parenchymal invasion (measured by edema on MRI) and poor prognosis in GBM. The specific aim of the present analysis was to determine the mechanistic impact of POSTN on glioma outcome. Methods: We used the gene expression of POSTN from 559 GBM patients (pts) included in the Cancer Genome Atlas (TCGA) to build a gene expression model of the expression of 12184 genes to predict POSTN expression using elastic net. This model was used to predict the POSTN expression in a testing set of 419 pts with gliomas included in Repository for Brain Neoplasia Data (REMBRANDT) (99 grade II, 71 grade III and 125 grade IV and 124 with no grade). Receiver-operating characteristic (ROC) and survival analysis were performed to measure the performance of the model, and gene-set enrichment analysis (GSEA) was used to reveal network topology perturbations. Results: The gene expression model discovered 721 genes highly correlated to POSTN expression that predict POSTN in the testing set with an area under the curve (AUC) of 0.96 on ROC curve. GSEA reveals genes involved in “mesenchymal transition,” transition of invasive ductal carcinoma (IDC) from ductal carcinoma in situ (DCIS) in breast cancer and stem cell signatures. Survival analysis of the TCGA GBM pts showed that the cohort with “high POSTN” had worse survival (median 12 months versus 15 months, log-rank p=0.0002). When applied to all pts in REMBRANDT, the model predicted classes also had significantly different survival (median 13.4 versus 38 months, log-rank p Conclusions: We have developed a gene expression model related to POSTN, a gene linked to poor prognosis in GBM, to investigate the role correlated genes may play in the aggressive phenotype. Some of the genes found to be highly correlated to POSTN are related to mesenchymal transition, invasive behavior in breast cancer and stemness. We verify that high POSTN expression is a strong prognostic indicator for poor outcome in GBM, and reveal for the first time that pts with grade II and III glioma with a “high” POSTN signature have significantly worse survival. Given that low grade glioma pts often have less aggressive treatment at time of diagnosis, we propose studying the role of early chemoradiation in the subset of pts with poor POSTN signature to potentially improve their outcome. Citation Format: Andrew D. Trister, Andrei M. Mikheev, Jason K. Rockhill, Stephen H. Friend, Robert C. Rostomily. Periostin expression in glioma correlates with genes related to mesenchymal transition and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1210. doi:10.1158/1538-7445.AM2013-1210

Using Quantitative Trait Locus (QTL) mapping in a backcross between susceptible Fischer 344 and resistant Copenhagen rat strains, we identified Fry, the rat ortholog of the Drosophila melanoganster furry gene, as a mammary carcinoma susceptibility (Mcs) gene. The Fischer 344 Fry allele harbors two single nucleotide polymorphisms that alter amino acid residues that are highly conserved from yeast to humans. One of these SNPs replaces an Alanine with a Serine residue, creating a de novo concensus sequence for several cancer-associated protein kinases. In the lower eucaryoyes, the furry orthologs are implicated in diverse cell processes including epithelial cell polarization, morphogenesis, proliferation, cytokinesis, and regulation of the NDR family of kinases, some of which are putative human tumor suppressor genes. Consistent with its function as a tumor suppressor gene, ectopic expression of the FRY gene was reduced in 3 of 4 human breast cancer cell lines. Ectopic expression of the wildtype allele significantly reduced the tumorigenicity of the human MDA-MB-231 mammary carcinoma cell line. In contrast to the parental MDA-MB-231 cells, which grew randomly in Matrigel® matrix, those expressing Fry (231CFry) formed spherical colonies of differentiated cells, closely resembling those formed by MCF-10A normal mammary epithelial cell line. When xenographed into nude mice, the 231CFry cells demonstrated a dramatic reduction in tumorigenicity (8x reduction in tumor volume at 15 days) and diminished invasiveness into surrounding tissues. Gene expression profiling suggested that in MDA-MB-231 cells, ectopic Fry induced the expression of gene networks involved in cell differentiation, proliferation, and polarization, consistent with a role for FRY in suppressing epithelial-mesenchymal transition (EMT). To investigate the role of human FRY in breast cancer, we examined FRY mRNA expression in >1,500 human breast cancers, representing distinct eight cohorts entered into the Oncomine 3.0 Cancer Profiling Database. Our analysis revealed that decreased FRY mRNA was highly correlated with poorly differentiated breast cancer phenotypes (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-131. doi:10.1158/1538-7445.AM2011-LB-131