Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era

Perry, C., Agarwal, D., Abdel-Fatah, T.M.A., Lourdusamy, A., Grundy, R., Auer, D.T., Walker, D., Lakhani, R., Scott, I.S., Chan, S., Ball, G. ORCID: 0000-0001-5828-7129 and Madhusudan, S., 2014. Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era. Oncotarget, 5 (14), pp. 5764-5781. ISSN 1949-2553

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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 and low PTEN remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas.

Item Type: Journal article
Publication Title: Oncotarget
Creators: Perry, C., Agarwal, D., Abdel-Fatah, T.M.A., Lourdusamy, A., Grundy, R., Auer, D.T., Walker, D., Lakhani, R., Scott, I.S., Chan, S., Ball, G. and Madhusudan, S.
Publisher: Impact Journals, LLC
Date: 2014
Volume: 5
Number: 14
ISSN: 1949-2553
Identifiers:
NumberType
10.18632/oncotarget.2180DOI
Rights: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.
Divisions: Schools > School of Science and Technology
Depositing User: Jill Tomkinson
Date Added: 09 Feb 2016 14:03
Last Modified: 09 Jun 2017 13:59
URI: http://irep.ntu.ac.uk/id/eprint/26916

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