Evaluation of expression of DNA repair molecules as a prognostic factor for long-term survivors with glioblastoma multiforme (GBM) treated on RTOG protocols with irradiation and nitrosoureas

Abstract

1509 Background: Adding BCNU to irradiation appears to modestly increase one and two year survival in GBM patients. BCNU attaches a chloroethyl adduct to the O6 position of guanine followed by formation of a DNA interstrand cross-link. These lesions may be repaired by alkyl-guanine transferase (AGT) and nucleotide excision repair (NER)/homologous recombinational repair (HRR) pathways, respectively. BCNU-initiated apoptosis signaling depends on intact DNA mismatch repair (MMR). Defects in MMR and intact NER/HRR and p53 expression may be linked to BCNU insensitivity. We hypothesized that these may also be prognostic factors in GBM. Methods: We compared the expression of AGT, ERCC1 (involved in the DNA nicking step of NER/HRR), the MMR proteins hMLH1 and hMSH2, and p53 between tumor samples, selected from the RTOG tissue bank, from 28 long term (>18 months) and 35 short term (< 6 months) GBM survivors receiving irradiation and nitrosoureas on RTOG protocols. Tumor cell nuclear expression was determined by immunohistochemistry using the Chromovision automated cell imaging system. Results: The two groups vary in age (p=0.003) and KPS (p=0.02) but not extent of resection (p=0.12). Conclusions: Within this patient population the levels of the DNA repair molecules examined do not predict for long term survivorship. No interaction between MMR and AGT was observed. Larger future studies should examine the expression of these and additional factors involved in the repair of nitrosourea induced DNA adducts. No significant financial relationships to disclose.