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.

Figure 1

Secondary glioblastomas develop in younger patients than primary glioblastomas. TP53 mutations occur in patients of any age group, whereas EGFR amplification occurs in older patients. Note that there is no single case of glioblastoma with EGFR amplification in patients younger than 35 years of age. (Modified from Ohgaki et al5).

Figure 2

Genetic pathways to primary (de novo) and secondary glioblastomas at the population level (Modified from Ohgaki et al5). LOH 10q is frequent in both primary and secondary glioblastomas. TP53 mutations are early and frequent genetic alterations in the pathway leading to secondary glioblastomas. *Genetic alterations that are significantly different in frequency between primary and secondary glioblastomas.

Figure 3

Major signaling pathways involved in the pathogenesis of glioblastomas.