BRAF alterations have been described in a wide spectrum of brain tumors, including in gliomas and glioneuronal tumors. BRAFV600E mutations have been found in approximately 10--15% of pilocytic astrocytoma and in approximately 5--10% of pediatric diffusely infiltrating gliomas, including diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III) and glioblastomas (WHO grade IV), but in less than 2% of comparable adult gliomas. This mutation is potentially targetable.

BRAF mutants, with a 3bp insertion between codons 599 and 600, display increased in vitro kinase activity activation potential comparable to those of BRAF V600E mutants.

Mutations in beta catenin (CTNNB1) are seen in about 90% of adamantinomatous craniopharyngiomas and mutations in BRAF (V600E) in papillary craniopharyngiomas. Adamantinomatous and papillary craniopharyngiomas have been shown to carry clonal mutations that are mutually exclusive. These findings indicate that the adamantinomatous and papillary subtypes have distinct molecular underpinnings, each principally driven by mutations in a single well-established oncogene - CTNNB1 in the adamantinomatous form and BRAF in the papillary form, independent of age. This may have implications for the diagnosis and treatment of these tumors.

EGFR mutations in GBM cluster in the extracellular (EC) domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). In vitro and in vivo studies reveal anchorage-independent growth and tumorigenic potential when the A289 and G598 variants are stably expressed in NIH-3T3 cells. The A289 and G598 mutations sensitize Ba/F3 cells to erlotinib in vitro according to some reports, although other reports state glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). The A289 variant has been reported to show sensitivity towards BAY846, a tyrosine kinase inhibitor in brain tumors. In addition, according to some reports, inhibitors which bind to the inactive EGFR conformation potently inhibit EGFR EC mutants and induce cell death in EGFR mutant GBM cells.

In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). EGFR exon 20 insertions have not been previously reported in GBM. The clinical significance of this mutation with regards to response to anti-EGFR therapy in GBM is unknown. In general, EGFR exon 20 mutations have been reported in approximately 9% of all EGFR-mutated cases of lung cancer and studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance or only partial response to approved EGFR-TKIs (erlotinib and gefitinib) in lung cancer.

In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). However, the p.E709K mutation in the tyrosine kinase domain of EGFR has not been previously reported in GBM. In vitro functional characterization of mutations at E709 have been reported to be activivating mutations that are associated with sensitivity to EGFR inhibitors in vitro in some cell systems. The clinical significance of this mutation with regards to response to anti-EGFR therapy in GBM is unknown.

IDH1 or IDH2 mutations are found in >70% of lower grade diffusely infiltrative gliomas and in >90% of secondary glioblastoma. IDH mutational status has been reported to be a favorable prognostic indicator relative to wild-type gliomas of similar histology, regardless of grade. Therapeutic strategies exploiting mutated IDH protein, including through direct inhibition and vaccine-based approaches, are currently the subject of preclinical research and clinical trials.

IDH1 or IDH2 mutations are found in >70% of lower grade diffusely infiltrative gliomas and in >90% of secondary glioblastoma. IDH mutational status has been reported to be a favorable prognostic indicator relative to wild-type gliomas of similar histology, regardless of grade. Therapeutic strategies exploiting mutated IDH protein, including through direct inhibition and vaccine-based approaches, are currently the subject of preclinical research and clinical trials.

Greater than 40% of glioblastomas (GBM) harbor focal amplification of the EGFR locus and there is evidence to suggest that these are driver alterations in these patients, making the EGFR pathway a potential therapeutic target in some clinical settings. Moreover, this alteration is relatively specific for GBM with very few other diffusely infiltrative gliomas having been shown to carry focal amplification of this locus (<3%). In GBM, this alteration frequently occurs in combination with other alterations of EGFR including polysomy 7, intragenic inframe deletions (e.g. EGFRvIII), and/or somatic point mutations. Based on current evidence, the independent predictive value of EGFR amplification in GBM is unclear. The relationship between individual and concurrent EGFR alterations and clinical response to small molecular inhibitors targeting EGFR is currently under investigation in clinical trials.

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in pediatric solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers and promote constitutive, ligand-independent activation of this RTK. Recurrent activating point mutations are seen within kinase domain in both the hereditary and sporadic form of neuroblastoma cases (7-10%). According to some studies, the presence of an ALK aberration could be a biomarker of aggressive disease and inferior clinical outcome. Clinical trials of crizotinib in neuroblastoma are underway. The R1275Q mutation is most common variant among ALK-mutated neuroblastomas (33%), and is found in both sporadic and familial cases. The R1275 amino acid substitution lies within the activation loop and causes constitutive ligand-independent activation of this RTK. Both preclinical and clinical studies suggest that this mutation could be sensitive to ALK inhibition.

Some studies have demonstrated activity of sonic hedgehog pathway inhibitors in a subset of medulloblastomas harboring alterations in this pathway.

In AML, presence of exon 17 mutations in KIT may confer an adverse prognosis or increased relapse rate. However, its significance in brain tumors is yet to be determined.

PDGFRA amplification is reportedly present in up to 29% of pediatric and 21% of adult high-grade astrocytomas when assessed by fluorescent in situ hydridization. Copy number alterations of this gene have been reported in approximately 11% of adult glioblastoma making it the second most commonly altered receptor tyrosine kinase after EGFR. In those adult glioblastomas that are IDH-mutant, there is evidence to suggest that amplification of PDGFRA is associated with worse overall survival.

This gene is a known cancer gene. ARID1A/BAF250A subunit of the SWI/SNF (BAF) chromatin remodeling complex has emerged as recurrently mutated in a broad array of tumor types and a potential tumor suppressor. There is evidence indicating that ARID1A-mutated cancers may be subjected to therapeutic intervention.

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

CDKN2A H83Y lies within the ANK3 domain of the CDKN2A protein. H83Y confers a loss of function to the CDKN2A protein as demonstrated by loss of cell cycle control. The CDKN2A gene locus is altered in up to approximately 57% of glioblastoma, most commonly as a homozygous deletion, and frequently with concurrent deletion of the CDKN2B locus. CDKN2A/CDKN2B loss may be associated with increased sensitivity to CDK4/6 inhibitors. The efficacy and toxicity profiles of these inhibitors in the context of a variety of cancer types are currently under evaluation in clinical trials. CDKN2A mutations account for only 1-3% of glioblastomas and the clinical significance remains to be elucidated.

H3F3A K28M mutation (more commonly referred to as K27M) is a diagnostic parameter for the 2016 WHO-recognized entity, "Diffuse Midline Glioma H3 K27M-mutant", an astrocytic diffusely infiltrating tumor arising in the midline, typically within the brainstem, but also sometimes arising in the diencephalon or spinal cord. These tumors have a poor prognosis. The H3K27M alteration, which is characteristically heterozygous, leads to a decrease in overall H3K27me3 levels through dysregulation of the polycomb repressive complex 2 (PRC2), and a concurrent increase in H3K27 acetylation levels. Research is ongoing in an effort to develop ways to exploit this characteristic molecular alteration through targeted strategies.