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Pediatric low-grade gliomas can be molecularly stratified for risk
Rui Ryan Yang1,2,3, Abudumijiti Aibaidula3, Wei-Wei Wang4
1Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China.
Insights
Pediatric low-grade gliomas (PLGGs) with specific molecular biomarkers like TERT promoter mutations or ATRX loss show poor prognosis. Identifying these genetic markers aids in stratifying PLGGs for better clinical decision-making and treatment.
Area of Science:
- Pediatric neuro-oncology
- Molecular diagnostics
- Cancer genomics
Background:
- Pediatric low-grade gliomas (PLGGs) are histologically diverse with better prognosis than adult gliomas, yet some experience progression.
- Molecularly distinct from adult gliomas, the clinical significance of newly discovered biomarkers in PLGGs requires further investigation.
Purpose of the Study:
- To evaluate a panel of molecular biomarkers in a large cohort of pediatric low-grade gliomas.
- To examine the clinical relevance and prognostic value of these biomarkers in PLGGs.
Main Methods:
- Direct sequencing for TERT promoter (TERTp), H3F3A, and BRAF V600E mutations.
- Immunohistochemistry for ATRX nuclear loss.
- Fluorescence in situ hybridization (FISH) for CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification in 289 PLGGs.
Main Results:
- TERTp mutations (2.5%), H3F3A mutations (6.4%), ATRX loss (4.9%), and BRAF V600E mutations (7.4%) were associated with poor prognosis (shorter PFS and OS).
- KIAA1549-BRAF fusion (32.0%) and MYB amplification (10.6%) were favorable prognostic markers (longer PFS and OS).
- A risk stratification model was developed: low-risk (KIAA1549-BRAF fusion/MYB amplification), intermediate-I (BRAF V600E/CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp/H3F3A mutation/ATRX loss), showing distinct PFS and OS.
Conclusions:
- Molecular biomarkers significantly impact prognosis in pediatric low-grade gliomas.
- The identified biomarkers and proposed risk stratification scheme can aid in clinical decision-making for PLGG patients.
- Further research into these distinct molecular subgroups may lead to targeted therapies.
Abstract:
Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.
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