Abstract
Pilocytic astrocytoma (PA), a WHO grade I tumor, occurs rarely in adults and shows aggressive tumor behavior. However, their underlying molecular-genetic events are largely uncharacterized. Hence, we studied 59 adult PA patients of classical histology with MIB-1 LI from 1-5% (median age at diagnosis 30 yrs, age-range 19-69 yrs). BRAF alterations examined in 59 cases confirmed KIAA1549-BRAF fusion in 11(19%), BRAF-gain in 2(3.4%) by qRT-PCR, and BRAF-V600E mutation in 1(1.7%) case using direct sequencing. FGFR1-mutation and FGFR-TKD duplication were seen in 7/59(11.9%) and 3/59(5%) cases respectively. Notably, FGFR related genetic alterations were enriched in supratentorial region (8/25, 32%) as compared to other tumor locations (P = 0.01). The association of age with respect to FGFR1-mutation (Mean age ± SD: 37.2 ± 15) compared to cases with KIAA1549-BRAF (Mean age ± SD: 25.1 ± 4.1) was significant (P = 0.03). Further, BRAF + FGFR duplicate genetic alterations were identified in 3(5%) cases (all in supratentorial tumors). Overall 36% of adult PAs harbored BRAF and/or FGFR related genetic alterations. Immunopositivity of p-MAPK/p-MEK1 corresponding to MAPK/ERK pathway activation was found in all the cases examined. In total, mTOR activator, pS6-immunoreactivity of any degree was observed in 34/39(87%) of cases. Interestingly, cases with BRAF and/or FGFR related alteration showed significantly lower pS6 immunostaining (3/12, 25%) as compared to BRAF and/or FGFR wild-type (16/27;59%) (P = 0.04). This study represents the largest reported adult PA patient cohort molecularly profiled to date. PAs with classical histology occur in adults but harbor infrequent BRAF alterations but enriched FGFR alterations in most instances compared to pediatric. The activation of constitutive BRAF-FGFR related MAPK/ERK signaling along with mTOR appears to be an important oncogenic event in adult PAs and may be constituting to the aggressive tumor behavior of adults. Therefore this study provides a rationale for potential therapeutic advantage of targeting MAPK/ERK and mTOR pathway in adult PAs.
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