Genetic alterations related to BRAF-FGFR genes and dysregulated MAPK/ERK/mTOR signaling in adult pilocytic astrocytoma.
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.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Pankaj
P
Pathak
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.
Anupam
A
Kumar
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Prerana
P
Jha
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Suvendu
S
Purkait
Genomics and Molecular Medicine, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR- IGIB), New Delhi, India.
Mohammed
M
Faruq
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.
Ashish
A
Suri
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Vaishali
V
Suri
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Mehar C
MC
Sharma
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Chitra
C
Sarkar
D000328:Adult; D000367:Age Factors; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D012189:Retrospective Studies; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D055815:Young Adult
C546842:MTOR protein, human; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases
BRAF; FGFR1; MAPK/ERK; adult pilocytic astrocytoma; low grade glioma; mTOR