4. Activated Molecular Pathways in LGGs
In contrast to adult LGGs, the majority of pLGGs feature a unique activated signal transduction pathway, the RAS/MAPK (mitogen-activated protein kinase) pathway. In each case of pLGGs, only one variant genetic event could be observed, uniformly leading to the activation of the RAS/MAPK pathway. Therefore, pLGGs are regarded as “one-pathway diseases”
[4]. The RAS/MAPK pathway can be affected by numerous inhibitor agents targeting different levels of the activated pathway. At present, these inhibitor agents are under investigation in different phases of human clinical trials. Whenever possible, it is essential to identify the exact genetic alteration by tissue sample analysis to initiate targeted therapy.
The most common tumor predisposition syndrome is neurofibromatosis type 1 (NF1), which is the consequence of a germline mutation of
NF1, a tumor-suppressor gene located on chromosome 17. The
NF1 gene normally produces neurofibromin, a negative regulator of RAS protein. Failure of its suppression will activate RAS
[12]. It is known that 10–15% of children with NF1 will develop optic pathway LGG and an additional 3–5% will present LGG outside of the optic pathway, the latter with worse prognosis
[13][14]. LGG in NF1 could regress spontaneously, but in case of deterioration, as a first-line treatment, chemotherapy is applied (vincristine plus carboplatin or vinblastine in monotherapy) with strict avoidance of irradiation and without pretreatment biopsy
[15][16][17]. In NF1, LGGs containing genetic alterations activating the RAS/MAPK or other pathways and HGG could also occur. Recently, CNS tumor biopsy has been highly indicated in NF1, at least for a focused testing of mutations and to choose the best treatment option
[17].
The BRAF–KIAA1549 translocation is the most common molecular alteration in pLGG, which is the consequence of focal gains at 7q34, the location of the
BRAF gene
[4][18]. Due to the loss of the N-terminal regulatory domain of BRAF, downstream activation of the RAS/MAPK signaling pathway occurs
[19]. BRAF–KIAA1549 is most commonly observed in pilocytic astrocytoma and in tumors arising in the posterior fossa
[4]. Overall, 35% of pLGGs harbor this mutation
[13]. The common cerebellar localization and a well-circumscribed behavior, especially in pilocytic astrocytoma, make the complete surgical removal amenable and predispose to an excellent outcome without additional treatment. LGGs harboring the BRAF–KIAA1549 translocation in other locations with incomplete surgical removal still have a better outcome compared to those lacking this genetic alteration
[4][20]. Despite this, for tumors located in deep areas unfeasible for complete resection, progression could occur, and this may force additional therapy.
The BRAF V600E mutation in which a valine is replaced by glutamic acid at position 600 makes the MAPK/RAS pathway constitutively active. The BRAF V600E mutation as a molecular background for progression most commonly occurs in pleomorphic astrocytoma (77.8%), diffuse astrocytoma (43.5%), and ganglioglioma (49%) and is less common in pilomyxoid astrocytoma (13.3%), pilocytic astrocytoma (3%), and other LGGs, accounting for 15 to 20% of all pLGGs
[21][22]. Supratentorial tumors, in contrast to cerebellar lesions, more commonly harbor BRAF V600E than the BRAF–KIAA1549 translocation
[4]. pLGGs with the BRAF V600E mutation have a higher rate of local recurrence and a low overall survival rate after conventional treatment (irradiation, chemotherapy), despite their benign phenotype
[21]. BRAF V600E-mutated pLGGs with the presence of the CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A) deletion, more commonly described in pleomorphic xanthoastrocytoma, have a highly increased risk to transform to HGG in one or two decades
[4][23]. As the co-occurrence of CDKN2A deletion has only recently been described, the real genetic alteration leading to progression is still under debate
[24].
Activation of the RAS/MAPK pathway less frequently occurs at the receptor tyrosine kinase (RTK) level. FGFR1 (Fibroblast Growth Factor Receptor 1) plays a key role in signal transduction through the activation of its intramembranous domain
[25]. FGFR1 activating alterations are based on three different mechanisms: FGFR1 mutations (p.N546K, p.K656E), FGRFR1–TACC fusion, and FGFR1-TKD (tyrosine kinase domain) duplications
[22][26][27]. All these mechanisms could be assigned to typical histological subtypes, but non-exclusively. FGFR1 mutations most frequently (20%) accompany DNTs, other glioneuronal tumors, and tumors in midline brain structures, but they rarely occur in pilocytic astrocytomas and oligodendrogliomas
[4][13]. The FGFR1–TACC fusion most commonly occurs in pilocytic astrocytomas with a cystic lesion. FGFR1-TKD duplications, similarly to FGFR1 mutations, are most commonly (2–3%) present in DNTs and other glioneural tumors restricted to a cerebral hemisphere
[4][13][26]. FGFR1 alterations commonly cause the upregulation of the PI3K/Akt/mTOR pathway
[4]. FGFR1-mutated pLGGs have worse prognosis, but it is unclear if this is a consequence of reduced resection due to their midline localization or of the mutation itself
[28]. NTRK (Neurotrophic Tyrosine Receptor Kinase) fusions, activating the same pathways described for FGFR1 activation, less frequently occur in LGG
[4]. An ALK (Anaplastic Lymphoma Kinase) gene fusion has also been described in rare cases of gliomas, resulting in the activation of similar pathways. ALK fusion is mostly observed in infantile gliomas
[29].
Other genetic alterations are also observed in pLGGs. MYBL1 and c-MYB have less significant effect on survival, and there are typical mutations of adult LGGs identified in older children (IDH1, IDH2, H3F3a), with incompletely identified prognostic significance
[30]. Recent cIMPACT-NOW updates suggest creating a “pediatric-type” diffuse glioma group comprising histologically diffuse gliomas with BRAF V600E mutation (without CDKN2A/B homozygous deletion), FGFR1 alteration, or MYB and MYBL1 rearrangement
[31].
5. Conclusions
The recent advances in understanding the molecular background of pediatric gliomas are facilitating the application of effective drugs targeting the Ras/MAPK pathway, with fewer side effects in the case of pediatric low-grade gliomas, thus substituting harmful chemotherapy and irradiation. In the case of pediatric high-grade gliomas, understanding the molecular mechanism sustaining tumor progression and implementing recent advances to overcome the BBB may open novel therapeutic windows to treat these devastating diseases. The most promising approach is based on the highly immunogenic features of high-grade gliomas, which may be utilized by the reactivation of the ineffective self-protecting immune mechanisms or by applying other mechanisms such as CAR-T cell therapy or vaccination.