Molecular genetics of radiographically defined de novo glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) represents the final endpoint of anaplastic progression in astrocytomas. GBM which arise without clinical evidence of a prior low-grade astrocytoma (LGA) have been designated de novo GBM, and are thought to develop rapidly from initial tumour formation. However, a purely clinical definition of de novo GBM does not exclude a long-standing, asymptomatic low-grade tumour. This study therefore sought to determine the genetic features of a unique group of cases in which GBMs were documented to have arisen radiographically in defined period of time (radiographically defined de novo GBM). Clinical and genetic features were examined in a group of 11 patients with a histological diagnosis of high-grade astrocytoma at first biopsy and radiographically defined de novo GBM. The mean age of the patients at tumour diagnosis was 62 years (range 32-87). Six of 11 tumours arose in the temporal lobes. Eight of 11 tumours had epidermal growth factor receptor (EGFR) overexpression, and EGFR gene amplification was found in five of the six analysed cases. Overexpression of p53 was observed in only one tumour, and a TP53 mutation was present in this case. p16 immunostaining was undetectable in 10 cases, and homozygous deletion of CDKN2A was observed in four of the six studied tumours. pRb expression was lost in four tumours. Mutations in the PTEN gene were detected in two of six cases. The results in this unique group of cases confirms the prior hypothesis that the profile of genetic alterations in de novo GBM is distinct from that of GBM arising from a known LGA, and that these specific genetic pathways promote the rapid development of GBM.

Protein patterns and proteins that identify subtypes of glioblastoma multiforme

“…In general, the former tend to occur in older patients, to arise suddenly, and to pursue an aggressive course; on the other hand, secondary GBMs tend to occur in younger patients, evolve out of a lower grade glial tumor, such as an astrocytoma, after several years latency, but then to behave essentially as ruthlessly as primary GBMs (Kleihues and Cavenee, 2000;Smith and Jenkins, 2000;Lacroix et al, 2001;Simmons et al, 2001;Smith et al, 2001;Kapoor and O'Rourke, 2003). The only difference in outcome between these two groups may be that younger patients, in whom secondary GBMs may be more likely, tend to have better performance status at the time of GBM presentation and to tolerate surgery and adjuvant therapies more robustly (Kleihues and Cavenee, 2000;Tortosa et al, 2000;Simmons et al, 2001;Smith et al, 2001;Batchelor et al, 2004). Nonetheless, a diagnosis of GBM, no matter the clinical presentation, carries with it a grave prognosis, with a 5-year survival rate of 5% or less (Kleihues and Cavenee, 2000;Lacroix et al, 2001;Simmons et al, 2001;Smith et al, 2001;van den Boom et al, 2003).…”

“…Nonetheless, a diagnosis of GBM, no matter the clinical presentation, carries with it a grave prognosis, with a 5-year survival rate of 5% or less (Kleihues and Cavenee, 2000;Lacroix et al, 2001;Simmons et al, 2001;Smith et al, 2001;van den Boom et al, 2003). The clinical picture of two different origins has been identified at the genetic level as well (Kleihues and Cavenee, 2000;Smith and Jenkins, 2000;Tortosa et al, 2000;Smith et al, 2001;Batchelor et al, 2004). In general, GBMs that arise from lower grade tumors acquire alterations in the p53 tumor suppressor gene early in their development; over time, as lower grade tumors become more malignant, they accumulate additional genetic defects in a variety of genes, such as p16, Rb (retinoblastoma), DCC (deleted in colon cancer), and PTEN.…”

“…In the primary GBMs, one protein, EGFR, was identified by 2-DGE and confirmed by immunohistochemistry and Western blotting, which highlights the central role that the EGFR-Ras-MAPK pathway plays in the genesis of these tumors (Bischoff and Plowman, 1999;Giles et al, 2003;Veeman et al, 2003;PubMed, 2004). By contrast, of the six proteins identified in specifically in secondary GBMs, one is associated with DNA repair (three of seven of the progressive tumors had received radiation prior to tissue collection), one with oxidative stress (DUOX2) and cell proliferation, another with transcriptional regulation (hnRNP A3), and a fourth with cell migration and invasion (the ADAMTS-19 precursor) Khatua et al, 2003;Nutt et al, 2003;van den Boom et al, 2003).…”

“…The only difference in outcome between these two groups may be that younger patients, in whom secondary GBMs may be more likely, tend to have better performance status at the time of GBM presentation and to tolerate surgery and adjuvant therapies more robustly (Kleihues and Cavenee, 2000;Tortosa et al, 2000;Simmons et al, 2001;Smith et al, 2001;Batchelor et al, 2004). Nonetheless, a diagnosis of GBM, no matter the clinical presentation, carries with it a grave prognosis, with a 5-year survival rate of 5% or less (Kleihues and Cavenee, 2000;Lacroix et al, 2001;Simmons et al, 2001;Smith et al, 2001;van den Boom et al, 2003). The clinical picture of two different origins has been identified at the genetic level as well (Kleihues and Cavenee, 2000;Smith and Jenkins, 2000;Tortosa et al, 2000;Smith et al, 2001;Batchelor et al, 2004).…”

Glioblastoma pediátrico: estudo clínico patológico de 12 casos com imunoistoquímica para proteína p53

“…Apesar do pouco conhecimento que se dispõe, conseguiu-se entender um pouco da biologia molecular em pacientes adultos [21][22][23][24][25][26] , numa tentativa de prever o prognóstico e tentar oferecer melhores alternativas terapêuticas. Permanece, no entanto, a dúvida de que aquela mesma via genética possa levar ao desenvolvimento de glioblastomas em crianças e, neste caso, se a mesma terapêutica mostrar-se-ia efi caz.…”