Integrating molecular analyses with the 2021 WHO classification of adult pilocytic astrocytomas
Beatriz Moreno-Torres1, Irene Manzano-Benito2,3, Diana Cantero4
1Pathology Department, Hospital Francesc de Borja, Gandía, Valencia, Spain.
Insights
Pilocytic astrocytomas (PAs) in adults share MAPK pathway alterations with pediatric cases, notably the KIAA1549::BRAF (K-B) fusion. The K-B fusion is not linked to poor outcomes in adult PAs, suggesting a single molecular driver.
Area of Science:
- Neuro-oncology
- Molecular pathology
- Genomics
Background:
- Pilocytic astrocytomas (PAs) are WHO grade 1 gliomas, common in children and rare in adults.
- Pediatric PAs often show MAPK pathway dysregulation, including BRAF alterations like KIAA1549::BRAF (K-B) fusion or V600E mutation.
- Adult PAs may have a worse prognosis, necessitating molecular characterization for accurate diagnosis and treatment.
Purpose of the Study:
- To investigate the molecular landscape of adult pilocytic astrocytomas.
- To identify frequent molecular alterations and compare them with pediatric cases.
- To evaluate the prognostic significance of molecular findings, particularly the K-B fusion, in adult PAs.
Main Methods:
- Gene-targeted next-generation sequencing was employed for adult PA molecular profiling.
- Specific gene tests were performed, including for K-B fusion, TERT promoter, and FGFR1 hotspot mutations.
- Histological review was conducted to exclude tumors mimicking PA.
Main Results:
- MAPK pathway alterations, particularly involving BRAF and NF1 genes, were the most frequent molecular findings (55%).
- The K-B fusion prevalence was higher than previously reported (>40%), possibly due to improved detection methods.
- Molecular alterations identified sometimes suggested differential diagnoses, highlighting limitations in the 2021 WHO classification for adult PA.
- After excluding mimetic tumors, no adult PA patients with K-B fusion experienced mortality within a mean follow-up of over 10 years.
Conclusions:
- Adult pilocytic astrocytomas exhibit frequent MAPK pathway alterations, similar to pediatric cases.
- The KIAA1549::BRAF (K-B) fusion is a significant molecular driver in adult PAs and is not associated with poor prognosis.
- These findings suggest that adult PAs, like pediatric ones, may be driven by a single molecular event, with K-B fusion indicating a favorable outcome.
Abstract:
Pilocytic astrocytomas (PAs) are benign grade 1 gliomas according to the World Health Organization (WHO). They are common in children but rare in adults in whom they may have a worse prognosis. Pediatric PAs are usually associated with dysregulation of the mitogen-activated protein kinase (MAPK) pathway, often involving BRAF alterations such as the KIAA1549::BRAF (K-B) fusion or V600E mutation. We investigated the molecular characteristics of adult PA using gene-targeted next-generation sequencing and specific gene tests, including for K-B fusion, TERT promoter, and FGFR1 hotspot mutations. The most frequent molecular alterations detected involved the MAPK pathway, particularly affecting BRAF and NF1 genes (55%). The prevalence of the K-B fusion (>40%) was higher than previously reported, likely due to challenges in detecting it. We identified molecular alterations in some cases that raised the differential diagnosis of other tumor types, revealing limitations in the 2021 WHO classification for adult PA. After removing other diagnostic types that may mimic PA histology, no adult patients with a diagnosis of PA and K-B fusion died after more than 10 years of mean follow-up. These findings suggest that, similar to pediatric cases, PA in adults may be driven by a single molecular hit, where the K-B fusion is not related to poor outcome.
