title: Using the apparent diffusion coefficient to identifying MGMT promoter methylation status early in glioblastoma: importance of analytical method.
abstract: BACKGROUND
  Accurate knowledge of O(6)-methylguanine methyltransferase (MGMT) gene promoter subtype in patients with glioblastoma (GBM) is important for treatment. However, this test is not always available. Pre-operative diffusion MRI (dMRI) can be used to probe tumour biology using the apparent diffusion coefficient (ADC); however, its ability to act as a surrogate to predict MGMT status has shown mixed results. We investigated whether this was due to variations in the method used to analyse ADC.
  
  
  METHODS
  We undertook a retrospective study of 32 patients with GBM who had MGMT status measured. Matching pre-operative MRI data were used to calculate the ADC within contrast enhancing regions of tumour. The relationship between ADC and MGMT was examined using two published ADC methods.
  
  
  RESULTS
  A strong trend between a measure of 'minimum ADC' and methylation status was seen. An elevated minimum ADC was more likely in the methylated compared to the unmethylated MGMT group (U = 56, P = 0.0561). In contrast, utilising a two-mixture model histogram approach, a significant reduction in mean measure of the 'low ADC' component within the histogram was associated with an MGMT promoter methylation subtype (P < 0.0246).
  
  
  CONCLUSIONS
  This study shows that within the same patient cohort, the method selected to analyse ADC measures has a significant bearing on the use of that metric as a surrogate marker of MGMT status. Thus for dMRI data to be clinically useful, consistent methods of data analysis need to be established prior to establishing any relationship with genetic or epigenetic profiling.
authors.affiliation: Centre for Clinical Research, University of Queensland Brisbane, Queensland, Australia.
authors.forename: Dayle
authors.initials: D
authors.lastname: Rundle-Thiele
authors.affiliation: Brain Cancer Research Unit, Queensland Institute of Medical Research Brisbane, Queensland, Australia.
authors.forename: Bryan
authors.initials: B
authors.lastname: Day
authors.affiliation: Brain Cancer Research Unit, Queensland Institute of Medical Research Brisbane, Queensland, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Stringer
authors.affiliation: Department of Radiation Oncology, Royal Brisbane and Women's Hospital Brisbane, Queensland, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Fay
authors.affiliation: Discipline of Clinical Pharmacology, School of Medicine and Public Health, University of Newcastle Newcastle, New South Wales, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Neurosurgery, Royal Brisbane and Women's Hospital Brisbane, Queensland, Australia.
authors.forename: Rosalind L
authors.initials: RL
authors.lastname: Jeffree
authors.affiliation: Queensland PET Service, Royal Brisbane and Women's Hospital Brisbane, Queensland, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Centre for Clinical Research, University of Queensland Brisbane, Queensland, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bell
authors.affiliation: CSIRO Digital Productivity Flagship, CSIRO Herston, Queensland, Australia.
authors.forename: Olivier
authors.initials: O
authors.lastname: Salvado
authors.affiliation: Centre for Medical Diagnostic Technologies in Queensland, University of Queensland Brisbane, Queensland, Australia.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Gal
authors.affiliation: Discipline of Medical Imaging, University of Queensland St Lucia, Queensland, Australia ; Department of Medical Imaging, Royal Brisbane and Women's Hospital Brisbane, Queensland, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Coulthard
authors.affiliation: Centre for Medical Diagnostic Technologies in Queensland, University of Queensland Brisbane, Queensland, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Crozier
authors.affiliation: CSIRO Digital Productivity Flagship, CSIRO Herston, Queensland, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rose
keywords: ADC; MGMT; diffusion MRI; glioblastoma