Another frequently reported FGFR alteration among LGNTs is mutation of two hotspot residues (N546 & K656) in the tyrosine kinase domain of
FGFR1, well-known to be activating and oncogenic [
6,
46,
57,
76]. These two residues are the most commonly mutated residues in
FGFR1 in human cancers and interestingly are described predominately in CNS tumors, mostly histologic pilocytic astrocytomas [
40,
78]. Somatic hotspot and germline mutations in
FGFR1 have also been implicated in the pathogenesis of DNET [
60]. Of note, encephalocraniocutaneous lipomatosis (ECCL) a sporadic neurocutaneous syndrome with features of disordered RAS-MAPK signaling, appears to be mediated in at least a subset of cases by these very
FGFR1 mutations (in mosaic, somatic distribution) and also carries an increased risk of low-grade gliomas, again predominately of pilocytic astrocytoma histology [
6,
8,
42,
54,
64]. It is emerging however, that while these
FGFR1-mutant tumors certainly can be described histologically and biologically as low grade, they are distinct from typical pilocytic astrocytoma (WHO grade I), which are predominately driven by
BRAF fusions. In fact, in some early studies,
FGFR1 mutation in pilocytic astrocytoma was associated with a significantly poorer prognosis, although sample size was small [
4]. While no specific differentiating histologic criteria have been reported, it has emerged that there are distinguishing clinicopathologic features of these tumors; subsequent larger studies have revealed that pilocytic astrocytoma with
FGFR1 mutation are predominately extracerebellar and frequently midline in location, (in contrast to
BRAF-fusion positive pilocytic astrocytomas, which predominate in the cerebellum) [
40]. At the same time, hotspot
FGFR1 mutations have also been observed in adult and pediatric HGG, at the level of GBM (WHO grade IV) [
12,
40,
57]. Notably,
FGFR1 hotspot mutations have been detected in up to 18% of adult midline glioma with high grade histology [
55]. These
FGFR1-mutant HGG frequently demonstrated a recurrent mutational profile in which H3 alterations (H3F3A K27M) and somatic mutations in
NF1 [
40] were detected. Although this profile can be seen in tumors histologically equivalent to pilocytic astrocytoma, the underlying molecular features are strongly suggestive of biologic overlap with diffuse midline glioma, H3 K27M-mutant (WHO grade IV) [
40,
65].
FGFR1 hotspot mutations have also emerged as a molecular hallmark of rosette-forming glioneuronal tumor (RGNT) [
26,
66]. RGNTs predominately affect young adults and are relatively rare neuroepithelial tumors with distinctive histologic features namely, the presence of neurocytes in rosettes or perivascular pseudo-rosettes in addition to an astrocytic component resembling pilocytic astrocytoma. It is on the basis of histology that the diagnosis is rendered. While in recent studies
FGFR1 hotspot mutations were invariably detected among RGNTs [
66], their presence is not currently required for the diagnosis, (and as previously discussed, is certainly not unique to RGNT). Moreover, while RGNT corresponds histologically to WHO grade I and is generally considered benign, dissemination and progression have been reported in rare instances [
1,
2,
62,
68,
74]. Of note, frequent co-mutation with
PIK3CA as well as
NF1 have been reported in RGNT [
66]. Mutation of PI3K pathway genes has been associated with aggressive clinical behavior in LGNTs, although further study is needed to determine their prognostic value in RGNT [
26,
61]. On the whole, while there is clearly a role for
FGFR1 hotspot mutations in the pathogenesis of LGNT, their specificity for low grade histology and clinical behavior is highly dependent on histologic features and broader molecular context.