INTRODUCTION
Low Grade Gliomas(LGG) are the most common brain tumor in children
accounting for about 50% of childhood brain tumors(1). A small
proportion of LGGs, 2.9%, have been known to transform to high grade
gliomas(HGG)(2) . Genetic markers like the BRAFV600E mutation, have been
associated with worse prognosis (3). These molecular studies generally
require tissue samples obtained from either a biopsy or resection.
Elevated intra-tumoral citrate levels measured noninvasively via
magnetic resonance spectroscopy(MRS) has been identified as a marker for
those LGG destined to display aggressive behavior(4). The biological
basis for the citrate elevation has not yet been fully elucidated but it
would appear from initial in vivo studies that the citrate may not be
generated at least in the short term from glucose metabolism (4, 5).
Recurring mutations with substitution of lysine by methionine at codon
27 in histone H3 variants (H3K27M) are found in about 78% of diffuse
intrinsic pontine gliomas (DIPG). In addition, up to 36% of
non-brainstem gliomas carry either the K27M or G34R/V mutations, a
mutation characterized by substitution of glycine at codon 34 by
arginine or valine. The median survival for these patients is about one
year (6-8) (9). Although H3K27M mutations were originally thought to be
specific to HGG histology, these mutations were subsequently identified
in histological low grade tumors and portended a worse prognosis(10-12).
The 2016 WHO Classification of Tumors of the Central Nervous System
recently recognized H3K27M mutant diffuse midline glioma as a distinct
entity and recommended grading as WHO Grade IV. The mechanism for
tumorigenesis for these histone mutations is still being explored but a
possible hypothesis is that the H3.3K27M mutation reprograms the
epigenetic landscape and gene expression, thus driving tumorigenesis
(13).
Determining and understanding the degree to which elevated citrate
levels and histone mutations co-occur or occur exclusive of each other
could potentially improve the presurgical risk stratification of these
patients and identify a molecular pathway which could lead to
therapeutic targets. We carried out a retrospective study to determine
if higher levels of citrate were associated with histone mutations in
pediatric gliomas.