title: An ANOCEF genomic and transcriptomic microarray study of the response to radiotherapy or to alkylating first-line chemotherapy in glioblastoma patients.
abstract: 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.
authors.affiliation: INSERM, U842, Lyon, F-69372 France. francois.ducray@chu-lyon.fr
authors.forename: François
authors.initials: F
authors.lastname: Ducray
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.forename: Olivier
authors.initials: O
authors.lastname: Chinot
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.forename: Carole
authors.initials: C
authors.lastname: Colin
authors.forename: Lucie
authors.initials: L
authors.lastname: Karayan-Tapon
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.forename: Michel
authors.initials: M
authors.lastname: Wager
authors.forename: François
authors.initials: F
authors.lastname: Vallette
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.forename: David
authors.initials: D
authors.lastname: Rickman
authors.forename: Emilie
authors.initials: E
authors.lastname: Thomas
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Delattre
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.forename: François
authors.initials: F
authors.lastname: Berger
mesh_terms: 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
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019941:Cyclin-Dependent Kinase Inhibitor p16
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