Exploration of Involved Key Genes and Signaling Diversity in Brain Tumors

Abstract

Brain tumors are becoming a major cause of death. The classification of brain tumors has gone through restructuring with regard to some criteria such as the presence or absence of a specific genetic alteration in the 2016 central nervous system World Health Organization update. Two categories of genes with a leading role in tumorigenesis and cancer induction include tumor suppressor genes and oncogenes; tumor suppressor genes are inactivated through a variety of mechanisms that result in their loss of function. As for the oncogenes, overexpression and amplification are the most common mechanisms of alteration. Important cell cycle genes such as p53, ATM, cyclin D2, and Rb have shown altered expression patterns in different brain tumors such as meningioma and astrocytoma. Some genes in signaling pathways have a role in brain tumorigenesis. These pathways include hedgehog, EGFR, Notch, hippo, MAPK, PI3K/Akt, and WNT signaling. It has been shown that telomere length in some brain tumor samples is shortened compared to that in normal cells. As the shortening of telomere length triggers chromosome instability early in brain tumors, it could lead to initiation of cancer. On the other hand, telomerase activity was positive in some brain tumors. It is suggestive that telomere length and telomerase activity are important diagnostic markers in brain tumors. This review focuses on brain tumors with regard to the status of oncogenes, tumor suppressors, cell cycle genes, and genes in signaling pathways as well as the role of telomere length and telomerase in brain tumors.

Keywords: Brain tumors; Cell cycle genes; Oncogenes; Signaling pathways; Telomerase activity; Telomere length; Tumor suppressor genes.

Fig. 1

Differentiation and molecular changes in gliomas and genetic pathways to primary (de novo) and secondary glioblastomas. TP53 mutations are early events in the pathway leading to secondary glioblastomas

Fig. 2

Comparison of genetic alterations in primary and secondary glioblastoma. EGFR amplification and PTEN mutations are common in primary glioblastomas, while TP53 mutations are more common in secondary glioblastomas. Mutations in TP53 occur early in development of secondary glioblastoma

Fig. 3

Comparison of epigenetic alterations in primary and secondary glioblastoma. Promoter methylation of some genes including p14, p16, and Rb was reported in primary and secondary glioblastoma with a higher rate in secondary glioblastoma

Fig. 4

Interactions of Rb and p53 pathways. ATM phosphorylates Mdm2, which is a negative regulator for p53 protein and, therefore, reduces p53 degradation. p53 acts as a transcription factor for p15, p16, and p21 genes which in their turn inhibit CDK4/6 and the formation of CDK/cyclin complexes. Active CDK/cyclin complexes lead to phosphorylation of Rb, the negative regulator of E2F, which is a transcription factor for genes of the S phase (data adapted from Collins 2004)

Fig. 5

PI3K-Akt signaling pathway. Binding of a growth factor triggers the phosphorylation of PIP₂ by PI3K. The reverse reaction is catalyzed by the tumor suppressor PTEN. PIP₃ binds to the PH domain of Akt and the subsequent phosphorylation at specific sites by two kinases, PDK1 and mTORC2, leads to activation of Akt. Downstream targets of Akt, including Rheb, GSK3, and FOXOs, promote cell survival through different pathways (data adapted from Georgescu 2010)