Genetic Pathways to Primary and Secondary Glioblastoma

Abstract

Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16(INK4a) deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C-->A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter ( approximately 70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

“…Details are presented in Table 2. 17,24 Our data may find an important relevance in anti-angiogenic therapeutics of cancer, presently based on angiogenesis inhibitors targeting the VEGF signalling pathway. Such treatments have been proven to be efficacious in patient survival, associated with a chemotherapy.…”

Strategy for surveying the proteome using affinity proteomics and mass spectrometry

“…Secondary GBMs (~ 5%) arise from lower grade astrocytomas. Each category, while heterogeneous, has been associated with distinct genetic changes [2]. Differences between genetic alterations in radiation-induced gliomas and those in their spontaneously occurring counterparts are particularly relevant and may shed light on their respective molecular pathogeneses.…”

Regulation of glioblastoma cell invasion by PKCι and RhoB

“…Two common genetic changes that have been identified in glioblastoma are mutation of PTEN and the amplification and mutation of the gene for the epidermal growth factor receptor (EGFR; Ohgaki and Kleihues, 2007). Both of these mutations have been linked to increased motility and invasion because of their aberrant activation of the phosphoinositide 3-kinase (PI3K) pathway (Tamura et al, 1999;Cai et al, 2005).…”