Elevated Citrate Levels and Histone H3K27M mutations in Pediatric
Midline Gliomas-Predictors of Adverse Outcome
Abstract
Background: Low Grade Gliomas(LGG) account for about 50% of childhood
brain tumors. Elevated citrate levels have previously been shown to be
markers for aggressive behavior in LGGs and the H3K27M and G34R/V
mutations have emerged as molecular drivers for pediatric high-grade
gliomas(HGG). Procedure: We retrospectively analyzed data from 25
patients with midline gliomas to determine whether citrate levels
measured through magnetic resonance spectroscopy(MRS) were associated
with histone mutations identified by immunohistochemistry. Results:
Median age was 6 years (range:0-16 years) with 13 males and 12 females.
Most of the patients 14(56%) had a LGG with the most common locations
being the thalamus 13(52%) and brainstem 7(28%). The majority had
undergone a biopsy 16(65%) or a partial resection 8(32%). Gross total
resection was achieved in only one patient(4%). The majority of the
patients received adjuvant chemotherapy and/or radiotherapy. Median
citrate levels trended higher in patients with HGG compared to those
with LGG (1.49vs0.93mmol/kg, p-value=0.16) and in patients with the
H3K27M mutation compared to those without (2.30vs0.80mmol/kg, p-value
0.26). Histological grading (LGGvsHGG) (OR: 3.96, 95% confidence
interval (CI):1.32-11.94), H3K27M mutation (OR:3.77, 95%
CI:1.05-13.61), and age (OR:1.12, 95%CI:1.00-1.25) were significant
adverse prognostic factors in univariate analysis but only the
histological grading remained significant in multivariate analysis.
Conclusion: We determined that H3K27M mutations and elevated citrate
levels were adverse prognostic factors in both patients with LGG and
HGG. Exploring the relation between these two markers in larger studies
could lead to a noninvasive way of predicting high risk behavior prior
to biopsy.