Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Abstract

Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients.

ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival

“…A recent study by Navarro et al reported a strong association between EGFR amplification (or EGFRvIII expression) and ADD3 copy number variations in GBM. Genetic clustering suggested the co-occurrence of both events in a subgroup of GBM, the cluster where patients were presented with the shortest survival ( 34 ). In accordance with this finding, GBMs with EGFR amplification are often accompanied by the complete loss of chromosome 10 and are considered the common phenotypic endpoint of different genetic pathways ( 35 , 36 ).…”

Potential Diagnostic and Clinical Significance of Selected Genetic Alterations in Glioblastoma

“…EGFR amplifications, commonly observed in GBM, have been shown by Matini et al to promote angiogenesis and vascular proliferation within the tumor [40] and are associated with poor survival [40,41]. Drugs that could block the EGFR pathway could, therefore, be useful in the treatment of GBM [40].…”

Molecular and Cellular Mechanisms of Glioblastoma

“…Navarro et al [18] showed that EGFRvIII mutation and ADD3 loss were bad prognostic markers in a series of glioblastomas studied by multiplex ligation-dependent probe amplification. From this result, we might understand the absence of effect of the inhibitors of receptor tyrosine kinases in those glioblastomas that do not present EGFR mutations.…”