title: Genomic predictors of patterns of progression in glioblastoma and possible influences on radiation field design.
abstract: We present a retrospective investigation of the role of genomics in the prediction of central versus marginal disease progression patterns for glioblastoma (GBM). Between August 2000 and May 2010, 41 patients with GBM and gene expression and methylation data available were treated with radiotherapy with or without concurrent temozolomide. Location of disease progression was categorized as within the high dose (60 Gy) or low dose (46 Gy) volume. Samples were grouped into previously described TCGA genomic groupings: Mesenchymal (m), classical (c), proneural (pn), and neural (n); and were also classified by MGMT-Methylation status and G-Cimp methylation phenotype. Genomic groupings and methylation status were investigated as a possible predictor of disease progression in the high dose region, progression in the low dose region, and time to progression. Based on TCGA category there was no difference in OS (p = 0.26), 60 Gy progression (PN: 71 %, N: 60 %, M: 89 %, C: 83 %, p = 0.19), 46 Gy progression (PN: 57 %, N: 40 %, M: 61 %,C: 50 %, p = 0.8) or time to progression (PN: 9 months, N:15 months, M: 9 months, C: 7 months, p = 0.58). MGMT methylation predicted for improved OS (median 25 vs. 13 months, p = 0.01), improved DFS (median 13 vs. 8 months, p = 0.007) and decreased 60 Gy (p = 0.003) and 46 Gy (p = 0.006) progression. There was a cohort of MGMT methylated patients with late marginal disease progression (4/22 patients, 18 %). TCGA groups demonstrated no difference in survival or progression patterns. MGMT methylation predicted for a statistically significant decrease in in-field and marginal disease progression. There was a cohort of MGMT methylated patients with late marginal progression. Validations of these findings would have implications that could affect radiation field size.
authors.affiliation: Department of Radiation Oncology, UNC School of Medicine, CB 7152, 101 Manning Drive, Chapel Hill, NC, 27599-7512, USA. jordan.holmes@unchealth.unc.edu.
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Holmes
authors.affiliation: Department of Radiation Oncology, UCSF School of Medicine, 1600 Divisadero St, San Francisco, CA, 94115, USA.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Paulsson
authors.affiliation: Department of Radiation Oncology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Brandi R
authors.initials: BR
authors.lastname: Page
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Hinson
authors.affiliation: Department of Medicine (Hematology & Oncology), Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.|Brain Tumor Center of Excellence, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Lesser
authors.affiliation: Department of Neurosurgery, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Laxton
authors.affiliation: Brain Tumor Center of Excellence, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.|Department of Neurosurgery, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Tatter
authors.affiliation: Brain Tumor Center of Excellence, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.|Department of Neurosurgery, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Debinski
authors.affiliation: Department of Radiation Oncology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.|Brain Tumor Center of Excellence, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D019175:DNA Methylation / Q000528:radiation effects; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D018450:Disease Progression; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005500:Follow-Up Studies; D023281:Genomics; D005909:Glioblastoma / Q000235:genetics* / Q000532:radiotherapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011878:Radiotherapy / Q000379:methods; D012189:Retrospective Studies; D016879:Salvage Therapy; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: Genomics; Glioblastoma; Patterns of progression