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.
Highlights
Gliomas are the most common primary central nervous system tumour in adults [1]
APE1, NBN, PMS2, methylguanine DNA methyltransferase (MGMT) and PTEN mRNA expression levels independently associated with poor prognosis in adult glioblastomas
Whereas MGMT is involved in direct repair [18], APE1 is critical for base excision repair (BER) [19], NBN is a component of the MRE11-RAD50-NBN (MRN) complex involved in DNA damage signalling [20], PMS2 is essential for mismatch repair (MMR) [21] and recent evidence suggests that nuclear PTEN has an important role in DNA double strand break repair and genomic stability [22,23,24]
Summary
Gliomas are the most common primary central nervous system tumour in adults [1]. Despite advances in surgery, chemotherapy and radiotherapy, patients with grade 3 gliomas (anaplastic astrocytomas, anaplastic oligodendrogliomas and anaplastic oligoastrocytomas) have a five year survival rate of 27% [2]. Proficient DNA repair may promote cancer cell survival leading to treatment resistance and poor clinical outcome. Despite potential MGMT status directed therapy most patients will eventually progress and succumb to the disease This is perhaps not surprising as only approximately 9% of all methyl adducts formed by temozolomide are O6-methylguanine lesions and the rest, including N7-methylguanine (the most common, ~70%) and N3-methyladenine, are processed through the DNA base excision repair (BER) machinery in cells [8, 9]. DNA repair status may predict resistance to therapy but recent emerging evidence suggests that loss of DNA repair function may lead to accelerated accumulation of mutations during cancer development that eventually drive a mutator phenotype characterised by aggressive biological behaviour and adverse outcomes in patients [14]
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