Early Genetic Changes Involved in Low-Grade Astrocytic Tumor Development

Abstract

Astrocytomas represent the most common form of glial tumors. The most malignant grade of these tumors, glioblastoma multiforme, may arise as a malignant progression from low-grade astrocytoma through anaplastic astrocytoma to secondary GBM, or else it may arise "de novo" as primary GBM. Both types of glioblastoma are usually histologically indistinguishable. However, distinct molecular alterations have been described between them that potentially allow differentiation between the two mechanisms of origin. Since malignant transformation is a multistep process, we summarize in this review the earliest genetic changes that seem to be involved in the appearance and development of low-grade astrocytic tumors, where early detection and treatment could be possible.

Epidemiology and Outcome of Glioblastoma

“…The majority of GBMs (90%) are primary (33), and patients with primary GBM tend to be older (mean age = 55 years) than those with secondary GBM (mean age = 40 years). Genetic alterations more typical for primary GBM are EGFR overexpression, PTN mutation, and loss of chromosome 10 (5, 6, 34, 35), whereas genetic alterations more commonly seen in secondary GBM include IDH1 mutations, TP53 mutations, and 19q loss (5,6,20,(36)(37)(38)(39). IDH1 mutation is associated with better outcome and increased overall survival (33).…”

“…The mesenchymal subtype is enriched in the gene expression pattern of astrocytes as well as microglial markers. Proneural subtype is enriched in proneural genes expressed in oligodendrocytes and characterized by alterations in TP53, platelet-derived growth receptor (PDGFR), and ILDH1 (5,8,(35)(36)(37). The proneural subtype is also associated with younger age at diagnosis (31).…”

High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas

“…Although TP53 and PTEN mutations are common in higher grade gliomas (Cheng et al, 2000;Tada et al, 2003;Arjona et al, 2006), these genes are rarely altered in PA (Ishii et al, 1998;Hayes et al, 1999;Cheng et al, 2000;von Deimling et al, 2000;Wemmert et al, 2006). Similarly, although chromosomal aberrations or amplification/deletion of specific genes related to cell cycle control, growth factor receptors and signal transduction pathways are commonly identified in other glioma subtypes (Koschny et al, 2002;Schmidt et al, 2002;Ohgaki et al, 2004;Ohgaki, 2005), most cytogenetic studies have shown that the majority of PAs have normal karyotypes.…”

Genetic Diversity of Glioblastoma Multiforme: Impact on Future Therapies

“…The Proneural subtype was associated with younger age, PDGFRA abnormalities, IDH1 and TP53 mutations, all of which have been associated with secondary GBM in earlier studies (Arjona et al, 2006;Furnari et al, 2007;Kleihues and Ohgaki, 1999;Watanabe et al, 1996;Yan et al, 2009). Verhaak et al (2010) concluded that tumors did not change class at recurrence, because recurrent tumors were found in all subtypes (Murat et al, 2008).…”