PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma

Abstract

High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.

Keywords: FISH; IDH1; PDGFRA; astrocytoma; isocitrate dehydrogenase 1; prognosis.

Figure 1

Determination of PDGFRA copy number gain/amplification by fluorescence in situ hybridization. Fluorescent images illustrating the different patterns of PDGFRA amplification in high‐grade astrocytomas. A. Normal, no increase in PDGFRA signals. B. Polysomy, >10% of cells with >2, but <6 signals for both PDGFRA and centromere enumerating probe (CEP4). C. The most frequent pattern of low‐level amplification, innumerable PDGFRA signals in <10% of cells. D. Another pattern of low‐level amplification, >40% cells with ≥6 signals (a few signals are beyond the plane of focus). E. High‐level amplification, > 10% cells with >12 or innumerable PDGFRA signals. F. Rare tumors demonstrated high‐level co‐amplification of PDGFRA and CEP4. Amp. denotes PDGFRA amplification. PDGFRA probe (red) and CEP4 (green), magnification ×1000.

Figure 2

Pediatric high‐grade astrocytomas patients have similar overall survival with and without PDGFRA amplification. A. Pediatric patients with glioblastoma (GBM) with (n = 13) and without (n = 16) PDGFRA amplification have no significant difference in overall survival based on Kaplan–Meier survival analysis, P = 0.97. B. Kaplan–Meier survival analysis examining overall survival for pediatric patients with anaplastic astrocytoma with (n = 9) and without (n = 25) amplification of PDGFRA, P = 0.21. AA = anaplastic astrocytoma.

Figure 3

PDGFRA amplification is associated with worse overall survival in adult isocitrate dehydrogenase 1 (IDH1^R132H) mutant glioblastoma (GBM). (A) Kaplan–Meier survival analysis of patients with de novo GBM demonstrates no significant difference in overall survival for patients with (red, n = 34) and without (blue, n = 114) PDGFRA amplification, P = 0.45. (B) Comparison of overall survival in larger cohort of patients stratified for IDH1 mutation (IDH1^R132H) demonstrating decreased survival in IDH1 mutant GBM with PDGFRA amplification (red, n = 16) as compared with those without PDGFRA amplification (blue, n = 22) by Kaplan–Meier survival analysis, P = 0.023. Survival curves are also shown for IDH1 non‐mutant GBM with (green, n = 29) and without (black, n = 108) PDGFRA amplification. A similar analysis in adult patients with anaplastic astrocytoma (AA) demonstrated overall survival was similar regardless of PDGFRA amplification in (C) all patients [amplified, red (n = 11); not amplified, blue (n = 58) ] and in (D) patients stratified for IDH1 mutation status [IDH1 mutant and amplified, red (n = 9); IDH1 mutant and not amplified, blue (n = 45); IDH1 non‐mutant and amplified, green (n = 2); IDH1 non‐mutant and not amplified, black (n = 21) ] by Kaplan–Meier survival analysis, P = 0.41 or 0.52, respectively.