NF1 is associated with tumors of the peripheral and central nervous system (CNS). The most common CNS tumors in NF1 are gliomas, which are seen in approximately 20% of patients
[16,17][16][17]. Gliomas usually affect children, with mean age at diagnosis of 4.5 years; the vast majority of such tumors originate within the optic nerves, optic chiasm, and/or hypothalamus. While individuals with NF1 are at higher risk for developing low-grade gliomas compared to high-grade gliomas
[18[18][19],
19], their risk for high-grade glioma is increased by 50-fold when compared to the general population
[20,21][20][21]. Indeed, high grade gliomas are rare tumors and the reported higher risk in children and adults with NF1 is based on epidemiologic studies and several case series
[22].
The World Health Organization (WHO) classification of gliomas has been refined and incorporated molecular parameters, namely 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M, in addition to histology to define many tumor entities
[23]. In general, low-grade gliomas form a group of WHO grade I and grade II tumors while high-grade gliomas form a group of WHO grade III and IV based on malignancy grade, molecular markers and presumed cell of origin. The most common glioma associated with NF1 is pilocytic astrocytoma, a WHO grade I tumor, with the optic pathway glioma being a hallmark lesion
[24]. Another low-grade astrocytoma that was reported in children with NF1 is pilomyxoid astrocytoma and the grading was suppressed in the revised 2016 WHO Classification to WHO grade I
[25]. In contrast to pilocytic astrocytomas, diffuse astrocytomas, which form WHO grade II, III and IV tumors, are more common in adult individuals with NF with only 12% presenting before the age of 20
[26]. A clinicopathologic study that examined tumors from 100 individuals with NF1 reported pilocytic astrocytoma frequency to be 49% while diffuse astrocytoma to be 27% which included WHO grade II (5%), III (15%), and IV (7%) though this grading used the 2007 WHO Classification
[26]. A recently published comprehensive genomic study performed in 23 high grade and 32 low-grade gliomas in individuals with NF1 demonstrated that children developed mostly low-grade gliomas (i.e., 77% of pediatric gliomas were low grade) whereas 78% of tumors in adults were high-grade
[27]. The study included whole exome sequencing of tumor and matched blood germline DNA to identify germline and somatic single nucleotide variants, small insertions and deletions, and copy number variants. The
NF1 variants observed in germline DNA were typically truncating and led to frameshifts, which did not cluster into specific NF1 protein domains. There was no association between particular patterns of
NF1 genetic variants and the risk of developing glioma. The data supported prior reports that a “second-hit” is required to develop tumors
[28], as loss of heterozygosity in the
NF1 region was detected in the majority of tumors. NF1-associated gliomas were found to have distinct genetic signatures, distinguishing them from those observed in sporadic gliomas, as well as noted to display different genetic landscapes when comparing low- vs. high-grade gliomas. For example, the isocitrate dehydrogenase (IDH) gene mutations (IDH1 and IDH2) are detected in more than 70% of sporadic low-grade gliomas and in the majority of glioblastomas arising from lower grade gliomas
[29]. Indeed, individuals with gliomas harboring IDH mutations have better prognosis than those with IDH wild-type
[30]. IDH mutations were not detected in gliomas associated with NF1 regardless of grade (). This finding may, in part, explain the observation that astrocytomas behave more aggressively than anticipated in adults with NF1
[31]. Another example is that mutations in H3.3 histone genes, frequently found in sporadic pediatric gliomas
[32], were absent in all samples regardless of age. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway, while high-grade tumors were characterized by a higher mutation burden and frequent mutations of
ATRX, typically co-occurring with alterations of
TP53 and cyclin-dependent kinase Inhibitor 2A (
CDKN2). DNA methylation assigned NF1-glioma to LGm6, a poorly defined IDH wild-type subgroup enriched with
ATRX mutations, which may represent a point of therapeutic intervention, as previous studies have shown that loss of ATRX increases sensitivity to DNA-damaging agents
[33,34][33][34]. summarizes the common molecular differences between NF1-associated gliomas and the LGm6 subgroup of sporadic gliomas
[27,35][27][35].
Figure 2. Optic pathway glioma and a high-grade cerebellar glioma in a young adult with NF1. (
A) MRI brain, axial T2 sequence showing hyperintense left optic nerve lesion (arrow) and ill-defined hyperintense lesion within the left cerebellum (asterisk) associated with mass effect. (
B) Post-contrast T1 sequence showing heterogeneous enhancement of the left cerebellar lesion concerning high grade neoplasm (asterisk). Histopathologic evaluation of the left cerebellar lesion was consistent with glioblastoma, WHO grade IV, IDH wild-type (
C) Infiltrating glioma exhibiting atypical cells and vascular endothelial proliferation (H&E, 200×). (
D) Tumor cells are negative for IDH1 (R132H) mutant protein (IHC, 200×).
Table 1. Somatic and Germline alterations in NF1-Glioma compared to the LGm6 subgroup of sporadic gliomas.
Variation |
NF1-Glioma |
LGm6 Sporadic Glioma |
High Grade |
Low Grade |
High Grade |
Low Grade |
|
|
Grade IV |
Grade III |
Grade II |
IDH Wild-Type |
100 |
100 |
100 |
100 |
100 |
TERT |
47 |
12 |
43 |
|
|
ATRX |
42][41][42]. A large cohort study that examined
NF1 mutations in 215 NF1 patients (100 of them had OPGs) observed that those with variants in the cysteine/serine-rich domain of the
NF1 gene (CSRD, residues 543–909), which is located in 5′ tertile, had higher risk of developing OPGs
[39]. A recent genotype-phenotype study reported a more severe phenotype in individuals with NF1 who carry missense mutations affecting one of five neighboring codons 844–848 located outside the GAP-related domain
[43]. The study presented 162 individuals heterozygous for a constitutional NF1 missense mutation in one of the five neighboring codons 844–848. The cluster of the recurrent missense mutations reported in this study involving aa 844–848 is located within the CSRD domain, which is likely functionally important, and was originally described by Fahsold et al.
[44]. The reported individuals have high prevalence of severe NF1 phenotype, including plexiform and/or spinal neurofibromas, symptomatic OPGs, skeletal abnormalities, and other malignant neoplasms.
Some studies of the tumor microenvironment have highlighted the role of microglia in OPGs, possibly due to the release of monocyte chemoattractant protein-1 (MCP-1) by the gliomas
[45,46][45][46]. Microglia can have an immunosuppressive role in the tumor microenvironment, through the release of Tumor Growth Factor beta (TGFβ), and Vascular Endothelial Growth Factor (VEGF); findings that raise the possibility of immunomodulation of microglia as a possible therapeutic target in NF1-associated gliomas ()
[47].
Table 2. Clinical trials for NF1 associated gliomas.
Drug |
Target |
Tumor |
Phase |
Age |
Endpoints |
Status |
Vinblastine +/− Bevacizumab NCT02840409 |
Cytotoxic/VEGF |
LGG |
II |
6 months to 18 years |
Response rate, OS, PFS, visual outcome measures, OCT |
Recruiting |
Pegylated interferon NCT02343224 |
Tumor microenvironment |
PA or OPG |
II |
3 to 18 years |
Response rate |
Recruiting |
38 |
3 |
13 |
42 |
0 |
Pomalidomide NCT02415153 |
Angiogenesis/immunomodulation |
NF1-associated CNS tumors |
I |
3 to 20 years |
Toxicity, MTD |
Active, not recruiting |
CDNK2A |
58 |
Lenalidomide NCT01553149 |
Angiogenesis/immunomodulation | 19 |
59 |
46 |
17 |
PA or OPG |
II |
0 to 21 years |
Response rate |
Active, not recruiting |
TP53 |
29 |
Everolimus (RAD0001) NCT01158651 |
mTOR | 0 |
35 |
42 |
0 |
LGG |
II |
1 to 21 years |
Response rate |
Active, not recruiting |
PTEN |
12 |
0 |
54 |
38 |
0 |
Binimetinib (MEK162) NCT02285439 |
MEK |
LGG |
1 to 18 years |
MTD, response rate |
Recruiting |
PIK3CA |
17 |
0 |
13 |
0 |
8 |
NF1 |
88 |
91 |
22 |
50 |
8 |
BRAF |
0 |
3 |
4 |
0 |
15 |
NF1 germline mutation |
92 |
91 |
|
|
Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltration, and increased neo-antigen load, implying that such tumors may also be targeted via immunotherapies. Such results were confirmed via immunohistochemistry for the T lymphocyte markers CD3 and CD8: the T-cell infiltrates in high-immune NF1-gliomas included cells positive for granzyme B, the cytolytic effector that is upregulated on CD8+ T-cell activation, while B lymphocytes (CD20) and macrophages (CD68) were rare both in high- and low-immune groups
[36].
Summary table listing the frequencies (%) of mutations seen in NF1-glioma as studied by D’Angelo, et al. (Nat Med, 2019), separated by high grade (Grade III–IV) and low grade (I–II). This molecular profile most closely correlated to the LGm6 subgroup of pan-glioma cohort from The Cancer Genome Atlas (TCGA) project (Ceccarelli, et al. Cell 2016), which is an IDH-WT group enriched with ATRX mutations.
TERT = TERT copy number variant gain in NF1-Glioma and TERT promotor expression in LGm6 group. ATRX = inactivation of ATRX from any mutation. CDNK2A = loss of copy number variant. TP53 = frameshift or missense mutation in both groups. PTEN = combination of missense and frameshift mutations in the NF-1 glioma group; missense and loss in LGm6 group. PIK3CA = missense and in-frame indel. NF1 = frameshift/truncating. BRAF = missense in NF1-glioma group, missense and frameshift in LGm6 group.
3. Optic Pathway Gliomas
Low-grade gliomas are the most common CNS tumors in the pediatric population, both in children with and without NF1
[37]. Multifocality and predilection for the optic pathways are features commonly associated with low-grade gliomas in NF1. Optic pathway gliomas (OPGs) are the most common brain tumors in individuals with NF1, with the majority classified as pilocytic astrocytoma (PA)
[38].
3.1. Genetic and Molecular Pathophysiology
Due to the tumor location, OPG surgery is rarely performed; therefore, there is a relative dearth of genomic and/or microenvironmental studies given the lack of tissue. Multiple studies have been conducted to identify genotype-phenotype associations in NF1-associated OPGs, but reports are conflicting, probably due to the smaller sample sizes
[39,40][39][40]. Studies have suggested that individuals with mutations in the 5′ tertile (exon 1-21) on
NF1 gene have a greater risk of developing OPG, but this was not confirmed in a subsequent study
[41,
Binimetinib (MEK162) NCT01885195 |
MEK |
Solid tumors with |
NF1 | mutation |
II |
Older than 18 years |
Response rate |
Completed (pending results) |
Selumetinib NCT01089101 |
MEK |
LGG |
I/II |
3 to 21 years |
Safety, MTD, Response rate |
Recruiting |
Selumetinib (Selumetinib vs. carboplatin and vincristine) Randomized NCT03871257 |
MEK |
OPG |
III |
2 to 21 years |
Event-free survival ∗, visual acuity |
Not yet recruiting |
TAK-580 NCT03429803 |
RAF (pan-RAF kinase inhibitor) |
LGG |
I/II |
1 to 18 years |
Toxicity, MTD, 6-month PFS |
Recruiting |