Progenitor-like traits contribute to patient survival and prognosis in oligodendroglial tumors.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore.
Felicia Soo-Lee
FS
Ng
Tan Boon
TB
Toh
Esther Hui-Ling
EH
Ting
Geraldene Rong-Hui
GR
Koh
Edwin
E
Sandanaraj
Mark
M
Phong
Swee Seong
SS
Wong
Siew Hong
SH
Leong
Oi Lian
OL
Kon
Greg
G
Tucker-Kellogg
Wai Hoe
WH
Ng
Ivan
I
Ng
Carol
C
Tang
Beng Ti
BT
Ang
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009837:Oligodendroglioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D051176:beta Catenin