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 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.

Methylation ofMGMTandADAMTS14in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans

“…However, even if the mutator role of MGMT hypermethylation appears modest, it may have a relevant prognostic value. Recent clinical studies showed that methylation of MGMT is a useful predictor of the responsiveness of tumors to alkylating agents in gliomas [ 45 , 46 ], and is associated with good survival in patients treated with multidrug regimens [ 47 ]. It also predicts the response to the alkylating drug dacarbazine in metastatic CRC [ 48 , 46 ].…”

“…Recent clinical studies showed that methylation of MGMT is a useful predictor of the responsiveness of tumors to alkylating agents in gliomas [ 45 , 46 ], and is associated with good survival in patients treated with multidrug regimens [ 47 ]. It also predicts the response to the alkylating drug dacarbazine in metastatic CRC [ 48 , 46 ]. In this context, the data on MGMT methylation and expression reveals a complex pattern of regulation and argues against a complete silencing in a significant proportion of methylated cases.…”

New insights into the genetics of glioblastoma multiforme by familial exome sequencing

“…PMS2 has been demonstrated to be important for GBM in various studies [31, 32]. Most interestingly, Walter and co-workers describe the case of a 13-year-old child presented with three simultaneous malignancies, including GBM.…”

DNA Repair Endonucleases: Physiological Roles and Potential as Drug Targets

“…Similarly, in patients who had received radiotherapy, low APE1 expression was significantly associated with decreased overall survival but was not significant in predicting survival in patients who had not received radiotherapy. 54 Furthermore, the significance of APE1 expression in breast cancer appears to be complex. Initial studies suggest that high APE1 expression indicates a poor prognosis in breast cancer, 55,56 whereas a more recent study conducted in a large cohort of breast cancers showed that low APE1 expression in estrogen receptor (ER)-positive tumors correlated with an aggressive phenotype and poor response to hormone therapy.…”