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Genetic evolution of diffusely infiltrating gliomas is mostly dependent on mutations of IDH1/IDH2. According to studies of newly diagnosed and recurrent neoplasms, this genetic event is likely to occur in the earliest stage of tumorigenesis, affecting common precursor cells that can give rise to both astrocytes and oligodendrocytes [6, 14, 22, 29, 30]. It is usually followed by the development of mutually exclusive TP53-ATRX or 1p/19q co-deletion-TERTmutational pathways, corresponding, respectively, to development of typical DA and “classic” OD (Fig. 2) [4, 31, 32]. These founder genetic events practically never demonstrate interregional variability within the tumor, whereas in general just 9.2% of all observed mutations are shared by all samplings from the same neoplasm, reflecting heterogeneity of gliomas [32]. The underlying causes of strong associations between molecular alterations and specific cell lineages of tumor differentiation remain unclear.

It is currently considered that histologically similar IDH1/IDH2-mutant and wild-type neoplasms represent distinct forms of diffusely infiltrating gliomas with different mechanisms of initiation and progression [13]. Of interest, some germline variants associated with glioma risk, namely CCDC26 (coiled-coil domain containing 26; rs55705857; located at 8q24.21) and PHLDB1 (pleckstrin homology-like domain, family B, member 1; rs498872; located at 11q23.3) are linked to development of gliomas carrying somatic IDH1/IDH2 mutations, whereas other germline variants, such as RTEL1 (regulator of telomere elongation helicase 1; rs6010620; located at 20q13), TERT (rs2736100) and CDKN2A/B (rs4977756) may be associated with the development of HGG, including pGBM. The mechanisms by which the inherited genetic events confer an increased risk of specific tumors are unknown [33].

Fig. 2. Model of molecular gliomagenesis. Diffusely infiltrating tumors are mostly dependent on mutations of IDH1/IDH2. MGMT promoter methylation is also considered as an early genetic event. Diffuse astrocytoma (DA) mainly develops through mutations of IDH1/IDH2, TP53, and ATRX, and oligodendroglioma (OD) through alterations of IDH1/IDH2, 1p/19q, CIC/FUBP1, and TERT promoter. The vast majority of primary glioblastomas do not carry IDH1/IDH2 mutations and their development is mainly associated with alterations of CDKN2A, TERT, PTEN, and EGFR. Circumscribed tumors, including pilocytic astrocytoma (PA) and pleomorphic xanthoastrocytoma (PXA) are also independent of IDH1/IDH2 mutations, but frequently carry alterations of BRAF. AA, anaplastic astrocytoma; OA, oligoastrocytoma; AOA, anaplastic oligoastrocytoma; AOD, anaplastic oligodendroglioma; mt, mutation; HD, homozygous deletion; meth, methylation; amp, amplification. Modified from Arita et al. [31].

Despite differences in transcriptomic profiles, WHO grades II and III gliomas of the same histological type are rather similar genetically (at least with regards to such founding events as alterations of IDH1/IDH2, TP53, ATRX, and 1p/19q) [9, 14, 32], thus they are frequently incorporated into a combined group of “lower-grade gliomas” in contrast to GBM. While additional molecular events play an important role in malignant progression, the early genetic alterations generally remain stable [30, 32]. Therefore, sGBM frequently carry mutations of IDH1/IDH2 (seen in two-thirds of cases [34]), TP53, and ATRX. Meanwhile, pGBM mostly display wild-type IDH, but frequently have mutations of TERT promoter and amplification of EGFR [12, 13, 31]. Approximately 5–8% of these tumors also carry IDH1/IDH2mutations [5, 35–37], but it should be borne in mind that “pGBM” is primarily a clinically defined entity, which presumes apparent absence of any preceding LGG. Since the presence of IDH1/IDH2mutations has been shown to be inversely related to, or even mutually exclusive of, such hallmarks of pGBM as mutation or HD of PTEN and amplification of EGFR[30], IDH1/IDH2-mutant pGBM should be preferably considered as “molecularly” sGBM, which is in line with the updated WHO classification of CNS tumors (2016) [11].

While the vast majority of IDH wild-type gliomas are pGBM, 16–30% of WHO grade II and III tumors also carry this genetic signature [7, 9, 13, 32]. Such neoplasms usually do not display TP53 mutation and 1p/19q co-deletion either. Among WHO grade II lesions such “triple-negative” gliomas are rare (7–9% of cases) [13, 22, 38]. AA carrying wild-type IDH frequently (>70% of cases) also demonstrate glioblastoma-like alterations of CDKN2A, PTEN, EGFR, etc., thus may be considered as variants or predecessors of WHO grade IV tumors [12, 13, 32]. Thus there might be a fraction of true sGBM that have progressed from lower-grade IDH wild-type astrocytomas [5].

Gliomas in children rarely demonstrate such molecular fingerprints as IDH1/IDH2 mutations and 1p/19q co-deletion, which suggests that distinct sets of genetic alterations underlie their unique clinicopathological characteristics. The ISN-Haarlem consensus guidelines [10] and the updated WHO classification of CNS tumors (2016) [11] presume the separation of some pediatric tumor entities from their adult counterparts. Low-grade pediatric astrocytomas exhibit fewer genetic abnormalities than tumors in adults and frequently carry alterations of BRAF, MYB (avian myeloblastosis viral oncogen homolog; located at 6q22-q23), MYBL1 (avian myeloblastosis viral oncogen homolog-like 1; located at 8q13.1), FGFR (fibroblast growth factor receptors) family, and infrequent TERT promoter mutations [14, 17, 39]. In cases of pediatric GBM and diffuse intrinsic pontine gliomas (DIPG) mutations of TP53, amplification of PDGFRA, as well as alterations in genes associated with histone-related functions and/or chromatin remodeling, e.g., H3F3A (H3 histone, family 3A; located at 1q42.12), ATRX, and DAXX (death-domain associated protein 6; located at 6p21.32), have been identified recently [17, 36, 40]. The updated WHO classification of CNS tumors (2016) [11] designates a new pathological entity, namely H3-K27M-mutant diffuse midline gliomas, since identification of this molecular abnormality provides a rationale for molecular targeted therapies. Of interest, some genetic alterations in pediatric gliomas depend not only on tumor histology, but also on location (Table 2) [13, 14, 17, 39]. Patient age also plays an important role, since tumors in teenagers tend to have more adult-type molecular features [14].

Table 2. Frequency of genetic alterations in pediatric low-grade gliomas with regard to tumor location (according to Ichimura et al. [14] and Fontebasso et al. [17])

Of note, a small subset of adult GBM may carry wild-type IDH combined with mutations of H3F3A and ATRX, thus exhibiting molecular features of pediatric HGG [12]. Moreover, thalamic HGG in adults may have genetic characteristics identical to DIPG in children, for example, H3F3A^K27M mutation, whereas hemispheric GBM frequently carry a different mutation (H3.3^G34R/V).