Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma.
OBJECTIVE
Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide.


METHODS
Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy.


RESULTS
An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response.


CONCLUSIONS
This study provides first clinical evidence for the implication of a "glioma stem cell" or "self-renewal" phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.
Laboratory of Tumor Biology and Genetics, Centre Universitaire Romand de Neurochirurgie, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne 1011, Switzerland.
Anastasia
A
Murat
Eugenia
E
Migliavacca
Thierry
T
Gorlia
Wanyu L
WL
Lambiv
Tal
T
Shay
Marie-France
MF
Hamou
Nicolas
N
de Tribolet
Luca
L
Regli
Wolfgang
W
Wick
Mathilde C M
MC
Kouwenhoven
Johannes A
JA
Hainfellner
Frank L
FL
Heppner
Pierre-Yves
PY
Dietrich
Yitzhak
Y
Zimmer
J Gregory
JG
Cairncross
Robert-Charles
RC
Janzer
Eytan
E
Domany
Mauro
M
Delorenzi
Roger
R
Stupp
Monika E
ME
Hegi
D000328:Adult; D053687:Adult Stem Cells / Q000473:pathology*; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D020869:Gene Expression Profiling; D005801:Genes, Homeobox; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D011836:Radiation Tolerance; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D066246:ErbB Receptors; D000077204:Temozolomide