title: Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era.
abstract: Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in 'The Cancer Genome Atlas' (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 (p=0.031) and low PTEN (p=0.042) remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas.
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Perry
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, UK.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: Children's Brain Tumour Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham University Hospitals, Nottingham, UK.
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.affiliation: Children's Brain Tumour Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham University Hospitals, Nottingham, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Grundy
authors.affiliation: Department of Academic Radiology, University of Nottingham, Nottingham University Hospitals, Queen's Medical Centre, Nottingham, UK.
authors.forename: Dorothee T
authors.initials: DT
authors.lastname: Auer
authors.affiliation: Children's Brain Tumour Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham University Hospitals, Nottingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Walker
authors.affiliation: University of Leicester Medical School, Maurice Shock Building, University Road, Leicester, UK.
authors.forename: Ravi
authors.initials: R
authors.lastname: Lakhani
authors.affiliation: Department of Neuropathology, Nottingham University Hospitals, Queen's Medical Centre, Nottingham, UK.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Scott
authors.affiliation: Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, UK; Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair; D005260:Female; D015870:Gene Expression; D023281:Genomics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor