Post-therapeutic changes in the molecular profile of glioblastomas

Abstract

2026 Background: Glioblastoma multiforme is the most common and malignant primary brain tumor in adults. Despite aggressive surgery, radiation, and chemotherapy, average survival time after diagnosis is about 1 year. This may be partly due to development of resistance to adjuvant therapies. While the molecular alterations in pretreated glioblastomas have been the subject of much research in recent years, changes in their genetic profile after adjuvant therapy are largely unknown. Methods: Herein we describe a cohort of over 40 glioblastomas with characterization of key genetic loci (EGFR, p53, 1p, 19q, 9p, 10q, 17p) using fluorescence in situ hybridization, PCR-based loss of heterozygosity (LOH) analysis, and immunohistochemistry on formalin-fixed, paraffin-embedded tissues. Analyses were performed on tumor tissue obtained at initial diagnosis and at first recurrence. Treatment regimen during the interval consisted of external beam radiation therapy and temozolomide, an alkylating chemotherapeutic agent. Results: About 50% showed large increases or decreases in hyperploidy of chromosomes 1, 7, 9, and/or 19 after therapy. Over 70% showed changes in LOH patterns on 1p, 19q, 9p, 10q, and/or 17p. 24% of previously non-EGFR-amplified tumors acquired low-grade amplification (less than 10 copies/chromosome 7 CEP signal) after treatment, and 16% of EGFR-amplified tumors lost amplification after treatment. Conclusions: Our results suggest that the molecular profile of these tumors is dynamic and that certain key alterations, including acquisition of low-level EGFR amplification in previously EGFR-negative tumors, occurs in a subset of cases. Such alterations may contribute to therapy resistance as the glioma evolves in a changing microenvironment. No significant financial relationships to disclose.