Low-grade gliomas in children in the era of molecular diagnostics

Scott Ryall of the University of Toronto, Canada, reviewed the molecular characteristics, targeted therapy pathways, corresponding detection platforms, and diagnostic treatment procedures of pLGG, which provided a decision-making basis
for the precise diagnosis and treatment of pLGG.

The article was published online in the March 2020 issue of Acta Neuropathologica Communications
.

- Excerpted from the article chapter

【Ref: Ryall S, et al.
Acta Neuropathol Commun.
2020 Mar 12; 8(1):30.
doi: 10.
1186/s40478-020-00902-z.
】

Research background

Central nervous system (CNS) tumors are common solid tumors in childhood; 5.
4-5.
6 cases
per 100,000 children.

Moreover, for every 100,000 children, 0.
7 people die from central nervous system tumors, making them the leading cause
of death from childhood tumors.

Low-grade gliomas in children (pLGG) are a common category of central nervous system tumors in children, accounting for about
30% of all childhood brain tumors.

pLGG belongs to WHO classes I and II and contains various pathological types of tumors throughout the nervous system (Figure 1).


The heterogeneity of its clinical behavior, especially for tumors that cannot be completely resected and are prone to recurrence, is a great challenge
.

Scott Ryall of the University of Toronto, Canada, reviewed the molecular characteristics, targeted therapy pathways, corresponding detection platforms, and diagnostic treatment procedures of pLGG, which provided a decision-making basis
for the precise diagnosis and treatment of pLGG.

The article was published online in the March 2020 issue of Acta Neuropathologica Communications
.

Figure 1.
Magnetic resonance imaging shows that low-grade gliomas in children occur in A.
cerebellum, B.
thalamus, and C.
occipital lobe
.

HE staining highlights the hallmark histological features of tumors: d.
hairy cell astrocytoma, e.
diffuse astrocytoma, f.
pleomorphic xanthoastrocytoma, g.
ganglion glioma, h.
embryonic dysplasia neuroepithelial tumor, i.
oligodendroglioma, j.
angiocentric glioma
.

Study results

The review is divided into the following parts:

First, molecular mutation spectrum

The molecular mutations of low-grade gliomas in children are fundamentally different
from those in adult patients.

Over the past decade, a large number of molecular data have shown that the RAS/MAPK pathway in pLGGs is regulated, with BRAF fusion or point mutations being the most common molecular feature in pLGGs, and BRAF V600E mutations having worse
overall survival (OS) and progression-free survival (PFS) compared to other pLGGs.

FGFR1 is the second most common molecular mutation in pLGG, including FGFR1 mutation, FGFR1-TACC1 fusion, and FGFR1 TKD-repeat.


FGFR1 mutations and FGFR1 TKD-duplications are common in dysplasia neuroepithelial tumors and other gliomas, while FGFR1-TACC1 is more common
in hair-cell astrocytomas.

Fusion of CRAF (RAF1) is rarely found in pLGG, but is common in
hair-cell astrocytomas.

These include QKI-RAF1, FYCO-RAF1, TRIM33-RAF1, SRGAP3-RAF1 and ATG7-RAF1
.

Due to the rarity of CRAF fusion, its clinical significance is unclear
.

The neurotrophic tyrosine receptor kinase (NTRK) gene family plays a key role
in central nervous system development.

NTRK fusions have been found in different histological subtypes of pLGG, including SLMAP-NTRK2, TPM3-NTRK1, ETV6-NTRK3, and RBPMS-NTRK3
.

Occurs less frequently, but has the potential to provide opportunities
for targeted therapies.

pLGG has a glioma associated with neurofibromatosis type I (NF1) caused by germline mutations in NF1; Among them, 10-15% of children with NF1 will develop low-grade gliomas within the optic pathway, and another 3-5% will develop outside
the optic pathway.

The course of NF1-pLGG is benign, but NF1-pLGG that occurs in younger children (2 years of age) or outside the optic nerve pathway carries a higher risk
of progression or death.

A recent study found that NF1-pLGG also has other genetic mutations, often affecting the RAS/MAPK pathway or variants involved in transcriptional regulators (Figure 2).

In addition, ALK fusion, ROS1 fusion, KRAS mutation, PTPN11 mutation, MAP2K1 mutation, MYB fusion, MYBL1 mutation and H3F3A mutation are also found
in some histological subtypes of pLGG.

Figure 2.
a.
Schematic diagram of the RAS/MAPK signaling pathway in low-grade gliomas in children; b.
Average RAS/MAPK mutation in low-grade gliomas in children; c.
Mutation types
of low-grade gliomas in children.

Second, targeted therapy

At present, the targeted therapies of pLGG mainly include BRAF, MEK, FGFR1 and ALK/ROS1/NTRK inhibitors
.

BRAF inhibitors such as dabrafenib and vemurafenib have been reported to be effective in case reports of monotherapy
.

A multicenter phase I clinical trial found an overall efficacy rate of up to 41%
with Dabrafenib.

Currently, a follow-up trial (NCT01677741)
to optimize dosing safety and tolerability is ongoing.

MEK inhibitors are promising treatments for pLGGs that are not suitable for BRAF inhibitors (NF1-pLGG, KIAA1549-BRAF fusion, etc
.
).

Currently, there are 4 MEK inhibitors: selumetinib, trametinib (NCT03363217), cobimetinib (NCT02639546) and binimetinib (NCT02285439) at various stages
of clinical trials.

Trials of the FGFR small molecule inhibitor AZD4547 for the treatment of malignant gliomas with FGFR-TACC fusion are ongoing
.

NTRK fusion is relatively rare in pLGG, and both entrectinib and larotrectinib show powerful antitumor effects (NCT02637687, NCT02576431).

3.
Detection method and platform

There is no "gold standard"
for pLGG molecular signature detection methods and platforms.

Currently, different test methods
are selected depending on the quality or quantity of the sample, the testing goal and the economic budget.

The authors summarize the cost, input requirements, limitations, and time requirements
of commonly used detection techniques for characterizing pLGG molecules.

Among them, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are commonly used methods, IHC can be used in most laboratories to timely and cost-effectively detect protein expression of potential mutations in tumors, widely used in the detection
of BRAF V600E, H3.
3 K27M and IDH1 R132H.

However, this approach is influenced by the detection of antibodies and is limited to available antibody variants
.

Fluorescence in situ hybridization (FISH) is used to detect gene fusion and copy number variation, and its detection can only target one reaction target
.

In recent years, the molecular identification of solid tumors using next-generation sequencing (NGS) platforms has been widely used
.

In these platforms, the design of the panel usually includes most of the mutation information
in the pLGG.

NGS-based methods facilitate the simultaneous acquisition of multiple variants in a single test, which can aid in making diagnostic, prognostic, and treatment decisions
.

A limitation compared to other techniques is that technical operation time and downstream analysis are more complex and time-consuming, but this is not a major problem
.

In addition, NGS is very advantageous
when other tests cannot identify pLGG molecular diagnostics.

4.
Molecular diagnosis and treatment process of pLGG

Given the molecular mutations in different tumor tissues and their overlap, the pLGG detection protocol is currently recommended, including detection of specific mutations in specific tissue types and the use of NGS panels containing information about mutations in pLGG (Figure 3).

Figure 3.
Decision tree
for molecular detection of low-grade gliomas in children.

*The frequency with which tumors carry FGFR1 mutations and other mutations suggests that testing is warranted regardless of status
.

AG: angiocentric glioma; dNet: neuroepithelial tumors of embryonic dysplasia; GNT: glial neuronal tumor; ODG: oligodendroglioma; PA: hairy cell astrocytoma; GG: ganglion glioma; PXA: pleomorphic xanthoastrocytoma; DA: diffuse astrocytoma
.

Conclusion of the study

Finally, the authors conclude that the association of targeted therapy with long-term sequelae is a matter of concern, particularly for radiation therapy, which may increase mortality
.

Therefore, more robust risk stratification is needed to help guide the type of treatment needed and the extent to
which it is performed.

In the past, prognosis
was judged based on surgical resection, histologic diagnosis, and age.

Recently, the molecular basis of pLGG has become a powerful tool
to complement tumor stratification.

With the advent of the era of targeted therapy, there is a need for a concise classification scheme
that can identify the molecular signature of pLGG.

Review the histological spectrum findings of pLGG, molecular mutations, and effective detections to evaluate the latest therapeutic agents and their role
in the treatment of this disease.

Finally, a multifaceted approach to pLGG stratification, including clinical, histological, and molecular parameters (Figure 4), is proposed to help clinicians make treatment decisions
.

Figure 4.
Risk relationship
for clinical and molecular characteristics of low-grade gliomas in children.

Points are awarded for showing tumor location, histology, age at diagnosis, and molecular drivers
.

The sum of points indicates a risk relationship, accompanied by clinical recommendations
for appropriate oncology treatment.

AG: angiocentric glioma; dNet: neuroepithelial tumors of embryonic dysplasia; GNT: glial neuronal tumors; ODG: oligodendroglioma; PA: hairy cell astrocytoma; GG: ganglion glioma; PXA: pleomorphic xanthoastrocytoma; DA: diffuse astrocytoma; DIA/DIG: connective tissue proliferative infantile astrocytoma/ganglion glioma; LGG: low-grade glioma; NOS: Not otherwise specified
.