title: A novel volume-age-KPS (VAK) glioblastoma classification identifies a prognostic cognate microRNA-gene signature.
abstract: BACKGROUND
  Several studies have established Glioblastoma Multiforme (GBM) prognostic and predictive models based on age and Karnofsky Performance Status (KPS), while very few studies evaluated the prognostic and predictive significance of preoperative MR-imaging. However, to date, there is no simple preoperative GBM classification that also correlates with a highly prognostic genomic signature. Thus, we present for the first time a biologically relevant, and clinically applicable tumor Volume, patient Age, and KPS (VAK) GBM classification that can easily and non-invasively be determined upon patient admission.
  
  
  METHODS
  We quantitatively analyzed the volumes of 78 GBM patient MRIs present in The Cancer Imaging Archive (TCIA) corresponding to patients in The Cancer Genome Atlas (TCGA) with VAK annotation. The variables were then combined using a simple 3-point scoring system to form the VAK classification. A validation set (N = 64) from both the TCGA and Rembrandt databases was used to confirm the classification. Transcription factor and genomic correlations were performed using the gene pattern suite and Ingenuity Pathway Analysis.
  
  
  RESULTS
  VAK-A and VAK-B classes showed significant median survival differences in discovery (P = 0.007) and validation sets (P = 0.008). VAK-A is significantly associated with P53 activation, while VAK-B shows significant P53 inhibition. Furthermore, a molecular gene signature comprised of a total of 25 genes and microRNAs was significantly associated with the classes and predicted survival in an independent validation set (P = 0.001). A favorable MGMT promoter methylation status resulted in a 10.5 months additional survival benefit for VAK-A compared to VAK-B patients.
  
  
  CONCLUSIONS
  The non-invasively determined VAK classification with its implication of VAK-specific molecular regulatory networks, can serve as a very robust initial prognostic tool, clinical trial selection criteria, and important step toward the refinement of genomics-based personalized therapy for GBM patients.
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, United States of America. zinn@bcm.edu
authors.forename: Pascal O
authors.initials: PO
authors.lastname: Zinn
authors.forename: Pratheesh
authors.initials: P
authors.lastname: Sathyan
authors.forename: Bhanu
authors.initials: B
authors.lastname: Mahajan
authors.forename: John
authors.initials: J
authors.lastname: Bruyere
authors.forename: Monika
authors.initials: M
authors.lastname: Hegi
authors.forename: Sadhan
authors.initials: S
authors.lastname: Majumder
authors.forename: Rivka R
authors.initials: RR
authors.lastname: Colen
mesh_terms: D000368:Aged; D001932:Brain Neoplasms / Q000145:classification / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000601:surgery; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005786:Gene Expression Regulation; D005909:Glioblastoma / Q000145:classification / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000601:surgery; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011859:Radiography; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D035683:MicroRNAs; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes