title: A novel literature-based approach to identify genetic and molecular predictors of survival in glioblastoma multiforme: Analysis of 14,678 patients using systematic review and meta-analytical tools.
abstract: Glioblastoma multiforme (GBM) has a poor prognosis despite maximal multimodal therapy. Biomarkers of relevance to prognosis which may also identify treatment targets are needed. A few hundred genetic and molecular predictors have been implicated in the literature, however with the exception of IDH1 and O6-MGMT, there is uncertainty regarding their true prognostic relevance. This study analyses reported genetic and molecular predictors of prognosis in GBM. For each, its relationship with univariate overall survival in adults with GBM is described. A systematic search of MEDLINE (1998-July 2010) was performed. Eligible papers studied the effect of any genetic or molecular marker on univariate overall survival in adult patients with histologically diagnosed GBM. Primary outcomes were median survival difference in months and univariate hazard ratios. Analyses included converting 126 Kaplan-Meier curves and 27 raw data sets into primary outcomes. Seventy-four random effects meta-analyses were performed on 39 unique genetic or molecular factors. Objective criteria were designed to classify factors into the categories of clearly prognostic, weakly prognostic, non-prognostic and promising. Included were 304 publications and 174 studies involving 14,678 unique patients from 33 countries. We identified 422 reported genetic and molecular predictors, of which 52 had ⩾2 studies. IDH1 mutation and O6-MGMT were classified as clearly prognostic, validating the methodology. High Ki-67/MIB-1 and loss of heterozygosity of chromosome 10/10q were classified as weakly prognostic. Four factors were classified as non-prognostic and 13 factors were classified as promising and worthy of additional investigation. Funnel plot analysis did not identify any evidence of publication bias. This study demonstrates a novel literature and meta-analytical based approach to maximise the value that can be derived from the plethora of literature reports of molecular and genetic factors in GBM. Caution is advised in over-interpreting the results due to study limitations. Further research to develop this methodology and improvements in study reporting are suggested.
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia. Electronic address: matthew.thuy@gmail.com.
authors.forename: Matthew N T
authors.initials: MN
authors.lastname: Thuy
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Jeremy K T
authors.initials: JK
authors.lastname: Kam
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Geoffrey C Y
authors.initials: GC
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Tao
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Dorothy Q
authors.initials: DQ
authors.lastname: Ling
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Su Kah
authors.initials: SK
authors.lastname: Goh
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Papachristos
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Lipi
authors.initials: L
authors.lastname: Shukla
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Krystal-Leigh
authors.initials: KL
authors.lastname: Wall
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Nicolas R
authors.initials: NR
authors.lastname: Smoll
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Jones
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Njeri
authors.initials: N
authors.lastname: Gikenye
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Bob
authors.initials: B
authors.lastname: Soh
authors.affiliation: Department of Radiology, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Brad
authors.initials: B
authors.lastname: Moffat
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Johnson
authors.affiliation: Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Drummond
mesh_terms: D000328:Adult; D015415:Biomarkers; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D005909:Glioblastoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D015996:Survival Rate / Q000639:trends
chemical_list: D015415:Biomarkers; D005819:Genetic Markers
keywords: Adults; Glioblastoma; Meta-analysis; Neurosurgery; Survival; Systematic review