An ANOCEF genomic and transcriptomic microarray study of the response to radiotherapy or to alkylating first-line chemotherapy in glioblastoma patients.
BACKGROUND
The molecular characteristics associated with the response to treatment in glioblastomas (GBMs) remain largely unknown. We performed a retrospective study to assess the genomic characteristics associated with the response of GBMs to either first-line chemotherapy or radiation therapy. The gene expression (n = 56) and genomic profiles (n = 67) of responders and non-responders to first-line chemotherapy or radiation therapy alone were compared on Affymetrix Plus 2 gene expression arrays and BAC CGH arrays.


RESULTS
According to Verhaak et al.'s classification system, mesenchymal GBMs were more likely to respond to radiotherapy than to first-line chemotherapy, whereas classical GBMs were more likely to respond to first-line chemotherapy than to radiotherapy. In patients treated with radiation therapy alone, the response was associated with differential expression of microenvironment-associated genes; the expression of hypoxia-related genes was associated with short-term progression-free survival (< 5 months), whereas the expression of immune genes was associated with prolonged progression-free survival (> 10 months). Consistently, infiltration of the tumor by both CD3 and CD68 cells was significantly more frequent in responders to radiotherapy than in non-responders. In patients treated with first-line chemotherapy, the expression of stem-cell genes was associated with resistance to chemotherapy, and there was a significant association between response to treatment and p16 locus deletions. Consistently, in an independent data set of patients treated with either radiotherapy alone or with both radiotherapy and adjuvant chemotherapy, we found that patients with the p16 deletion benefited from adjuvant chemotherapy regardless of their MGMT promoter methylation status, whereas in patients without the p16 deletion, this benefit was only observed in patients with a methylated MGMT promoter.


CONCLUSIONS
Differential expression of microenvironment genes and p16 locus deletion are associated with responses to radiation therapy and to first-line chemotherapy, respectively, in GBM. Recently identified transcriptomic subgroups of GBMs seem to respond differently to radiotherapy and to first-line chemotherapy.
Ducray
François
F
INSERM, U842, Lyon, F-69372 France. francois.ducray@chu-lyon.fr
de Reyniès
Aurélien
A
Chinot
Olivier
O
Idbaih
Ahmed
A
Figarella-Branger
Dominique
D
Colin
Carole
C
Karayan-Tapon
Lucie
L
Chneiweiss
Hervé
H
Wager
Michel
M
Vallette
François
F
Marie
Yannick
Y
Rickman
David
D
Thomas
Emilie
E
Delattre
Jean-Yves
JY
Honnorat
Jérôme
J
Sanson
Marc
M
Berger
François
F
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies
D018906:Antineoplastic Agents, Alkylating; D019941:Cyclin-Dependent Kinase Inhibitor p16
Int J Cancer. 2008 Apr 15;122(8):1778-86
18076069
Nucleic Acids Res. 2003 Feb 15;31(4):e15
12582260
Clin Cancer Res. 2008 May 1;14(9):2623-30
18451225
Am J Pathol. 2007 May;170(5):1445-53
17456751
J Natl Cancer Inst. 2007 Oct 17;99(20):1544-50
17925535
Cancer Res. 2005 Mar 1;65(5):1678-86
15753362
Int J Cancer. 1998 Jul 3;77(1):47-54
9639393
Nature. 2008 Oct 23;455(7216):1061-8
18772890
Clin Cancer Res. 2004 Dec 15;10(24):8177-84
15623592
Neuro Oncol. 2010 Apr;12(4):320-7
20308310
Glia. 2006 Dec;54(8):850-60
16981197
Int J Oncol. 2001 Aug;19(2):359-65
11445852
J Neurooncol. 2007 Jun;83(2):173-9
17219056
Curr Opin Oncol. 2006 Nov;18(6):631-6
16988586
Mol Cancer. 2008 May 20;7:41
18492260
Cell Cycle. 2009 Oct 15;8(20):3274-84
19770585
Radiother Oncol. 2003 Apr;67(1):45-51
12758239
Cancer Res. 2005 Dec 15;65(24):11335-44
16357140
Cancer Res. 2004 Sep 15;64(18):6503-10
15374961
Cancer Cell. 2010 Jan 19;17(1):98-110
20129251
Neoplasia. 2005 Oct;7(10):883-93
16242071
Hepatology. 2007 Jan;45(1):42-52
17187432
Science. 2008 Sep 26;321(5897):1807-12
18772396
Clin Cancer Res. 2007 Dec 15;13(24):7341-56
18094416
J Clin Oncol. 2008 Jun 20;26(18):3015-24
18565887
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5814-9
15827123
Int J Cancer. 1998 Dec 18;79(6):640-4
9842975
N Engl J Med. 2005 Mar 10;352(10):997-1003
15758010
J Clin Oncol. 1990 Jul;8(7):1277-80
2358840
Science. 2005 Jan 7;307(5706):58-62
15637262
Cancer. 2006 May 15;106(10):2218-23
16568472
Bioinformatics. 2006 Apr 1;22(7):849-56
16434445
J Clin Oncol. 2007 Sep 10;25(26):4033-42
17827451
Cancer Res. 2003 Apr 1;63(7):1602-7
12670911
Nat Rev Neurosci. 2007 Aug;8(8):610-22
17643088
Mol Cancer. 2006 Dec 02;5:67
17140455
Cancer Cell. 2006 Mar;9(3):157-73
16530701
Nature. 1992 Oct 29;359(6398):845-8
1279432
PLoS Med. 2006 Mar;3(3):e47
16417408
Nature. 1992 Oct 29;359(6398):843-5
1279431
Annu Rev Pathol. 2006;1:97-117
18039109
J Natl Cancer Inst. 2001 Feb 21;93(4):266-76
11181773
Cell Stem Cell. 2009 Mar 6;4(3):226-35
19265662
N Engl J Med. 2005 Mar 10;352(10):987-96
15758009