Genetic alterations related to BRAF‐FGFR genes and dysregulated MAPK/ERK/mTOR signaling in adult pilocytic astrocytoma

Abstract

Pilocytic astrocytomas occur rarely in adults and show aggressive tumor behavior. However, their underlying molecular-genetic events are largely uncharacterized. Hence, 59 adult pilocytic astrocytoma (APA) cases of classical histology were studied (MIB-1 LI: 1%-5%). Analysis of BRAF alterations using qRT-PCR, confirmed KIAA1549-BRAF fusion in 11 (19%) and BRAF-gain in 2 (3.4%) cases. BRAF-V600E mutation was noted in 1 (1.7%) case by sequencing. FGFR1-mutation and FGFR-TKD duplication were seen in 7/59 (11.9%) and 3/59 (5%) cases, respectively. Overall 36% of APAs harbored BRAF and/or FGFR genetic alterations. Notably, FGFR related genetic alterations were enriched in tumors of supratentorial region (8/25, 32%) as compared with other locations (P = 0.01). The difference in age of cases with FGFR1-mutation (Mean age ± SD: 37.2 ± 15 years) vs. KIAA1549-BRAF fusion (Mean age ± SD: 25.1 ± 4.1 years) was statistically significant (P = 0.03). Combined BRAF and FGFR alterations were identified in 3 (5%) cases. Notably, the cases with more than one genetic alteration were in higher age group (Mean age ± SD: 50 ± 12 years) as compared with cases with single genetic alteration (Mean age ± SD: 29 ± 10; P = 0.003). Immunopositivity of p-MAPK/p-MEK1 was found in all the cases examined. The pS6-immunoreactivity, a marker of mTOR activation was observed in 34/39 (87%) cases. Interestingly, cases with BRAF and/or FGFR related alteration showed significantly lower pS6-immunostatining (3/12; 25%) as compared with those with wild-type BRAF and/or FGFR (16/27; 59%) (P = 0.04). Further, analysis of seven IDH wild-type adult diffuse astrocytomas (DA) showed FGFR related genetic alterations in 43% cases. These and previous results suggest that APAs are genetically similar to IDH wild-type adult DAs. APAs harbor infrequent BRAF alterations but more frequent FGFR alterations as compared with pediatric cases. KIAA1549-BRAF fusion inversely correlates with increasing age whereas FGFR1-mutation associates with older age. Activation of MAPK/ERK/mTOR signaling appears to be an important oncogenic event in APAs and may be underlying event of aggressive tumor behavior. The findings provided a rationale for potential therapeutic advantage of targeting MAPK/ERK/mTOR pathway in APAs.

Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression

“…Except for ERK, the MAPK family in mammals includes c-Jun NH2-terminal kinase (JNK), p38 MAPK. It is demonstrated that ERK signaling closely integrates with mTOR signalings ( 26 , 27 ). Recently studies show that inhibition of p38 MAPK decreases sensitivity to PI3K/mTOR inhibition ( 28 ) and JNK contributes tumorigenic activity through mTOR pathway in cholangiocarcinoma ( 29 ).…”

“Integrated diagnosis” of pilocytic astrocytoma: Molecular diagnostic procedure for an unusual case

“…reported that 20% cases of adult PAs (9/45 tested) harbor KIAA1549‐BRAF fusion, which did not influence the outcome, while BRAF V600E mutations (0/40 tested) were not detected . Recent evidence demonstrated that FGFR1‐mutaion associates with older age of PAs, and activation of MAPK/ERK/mTOR signaling appears to be an oncogenic event in adult PAs . Meanwhile, it has been reported that non‐random aneuploidy correlates with older age, which preferentially affects non‐cerebellar PA and tumors with BRAF V600E, but not with KIAA1549‐BRAF fusion or FGFR1 mutation .…”

“…17 Recent evidence demonstrated that FGFR1-mutaion associates with older age of PAs, and activation of MAPK/ERK/ mTOR signaling appears to be an oncogenic event in adult PAs. 18 Meanwhile, it has been reported that nonrandom aneuploidy correlates with older age, which preferentially affects non-cerebellar PA and tumors with BRAF V600E, but not with KIAA1549-BRAF fusion or FGFR1 mutation. 19 Aneuploid PA differentially expresssed genes are involved in regulators of genomic stability and the cell cycle (MDM2 and PLK2), and may represent an additional molecular factor in older patients with PA. 19 Taken together, the data suggest that investigation of the status of BRAF gene is important to diagnose and predict the prognosis of PA patients.…”

Biomarkers in tumors of the central nervous system – a review

“…BRAF fusions are also less frequent in pilocytic astrocytomas of adults; Pathak et al. detected KIAA1549‐BRAF fusion in only 19% of adult cases.…”

“…Location is important, as 80% of pilocytic astrocytomas in the posterior fossa harbor BRAF fusions, while such fusions are only reported in 50% of pilocytic astrocytomas of the optic pathways and 25% of those located in the cerebral cortex (80). BRAF fusions are also less frequent in pilocytic astrocytomas of adults; Pathak et al (81) detected KIAA1549-BRAF fusion in only 19% of adult cases. Anaplastic astrocytoma with piloid features, also known as anaplastic pilocytic astrocytoma, is a controversial entity.…”