Progenitor-like Traits Contribute to Patient Survival and Prognosis in Oligodendroglial Tumors

• Published in: Clinical cancer research Vol. 18; no. 15; pp. 4122 - 4135
• Main Authors: NG, Felicia Soo-Lee, TAN BOON TOH, WAI HOE NG, NG, Ivan, TANG, Carol, BENG TI ANG, TING, Esther Hui-Ling, KOH, Geraldene Rong-Hui, SANDANARAJ, Edwin, PHONG, Mark, SWEE SEONG WONG, SIEW HONG LEONG, OI LIAN KON, TUCKER-KELIOGG, Greg
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2012
• Subjects: Animals; Antineoplastic agents; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Transformation, Neoplastic - genetics; Chromosome Deletion; Chromosomes, Human, Pair 1 - genetics; Chromosomes, Human, Pair 19 - genetics; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Immunoblotting; Kaplan-Meier Estimate; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oligodendroglioma - genetics; Oligodendroglioma - metabolism; Oligodendroglioma - pathology; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Prognosis; Receptors, Notch - genetics; Receptors, Notch - metabolism; Signal Transduction - genetics; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transplantation, Heterologous; Tumor Cells, Cultured; Wnt Signaling Pathway - genetics; Human; Prognosis; Stem cell; Patient; Malignant tumor; Survival; Cancer; Progenitor cell
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-3064

Patient-derived glioma-propagating cells (GPC) contain karyotypic and gene expression profiles that are found in the primary tumor. However, their clinical relevance is unclear. We ask whether GPCs contribute to disease progression and survival outcome in patients with glioma by analyzing gene expression profiles. We tapped into public sources of GPC gene expression data and derived a gene signature distinguishing oligodendroglial from glioblastoma multiforme (GBM) GPCs. By adapting a method in glioma biology, the Connectivity Map, we interrogated its strength of association in public clinical databases. We validated the top-ranking signaling pathways Wnt, Notch, and TGFβ, in GPCs and primary tumor specimens. We observed that patients with better prognosis correlated with oligodendroglial GPC features and lower tumor grade, and this was independent of the current clinical indicator, 1p/19q status. Patients with better prognosis had proneural tumors whereas the poorly surviving cohort had mesenchymal tumors. In addition, oligodendroglial GPCs were more sensitive to Wnt and Notch inhibition whereas GBM GPCs responded to TGFβR1 inhibition. We provide evidence that GPCs are clinically relevant. In addition, the more favorable prognosis of oligodendroglial tumors over GBM could be recapitulated transcriptomically at the GPC level, underscoring the relevance of this cellular model. Our gene signature detects molecular heterogeneity in oligodendroglial tumors that cannot be accounted for by the 1p/19q status alone, indicating that stem-like traits contribute to clinical status. Collectively, these data highlight the limitation of morphology-based histologic analyses in tumor classification, consequently impacting on treatment decisions.