Abstract 2406: Intra-tumoral heterogeneity of PDGFRA / MET gain in WHO grade II diffuse astrocytomas.
Authors: Motomura Kazuya , Mittelbronn Michel , Paulus Werner , Brokinkel Benjamin , Keyvani Kathy , Sure Ulrich , Wrede Karsten , Nakazato Yoichi , Tanaka Yuko , Nonoguchi Naosuke , Pierscianek Daniela , Kim Young-Ho , Mariani Luigi , Vital Anne , Perry Arie , Ohgaki Hiroko 
Published: August 2014

Abstract
Glioblastomas with a proneural expression signature are characterized by frequent IDH1 mutations (i.e. genetic hallmarks of secondary glioblastomas) and PDGFRA amplification. Most glioblastomas with IDH1 mutations (11/12, 92%) show a proneural signature, the majority with wild-type PDGFRA, while approximately 30% of glioblastomas with a proneural signature had IDH1 mutations. IDH1/2 mutations are frequent and early genetic events in diffuse astrocytomas WHO grade II, precursor to secondary glioblastomas, but little is known about the role and timing of PDGFRA amplification in these tumors.
In the present study, we assessed PDGFRA gain in 342 low-grade diffuse gliomas (166 low-grade diffuse astrocytomas, as well as 61 oligoastrocytomas and 115 oligodendrogliomas) by quantitative PCR. PDGFRA gain was detected in 27/166 (16.3%) diffuse astrocytomas, significantly more frequent than in oligoastrocytomas (6.6%; P=0.04) or in oligodendrogliomas (3/115; 2.6%; P&lt;0.0001).
We correlated PDGFRA gain with other genetic alterations in low-grade diffuse gliomas previously reported from our laboratory. PDGFRA gain was significantly more frequent in diffuse astrocytomas, oligodendrogliomas and low-grade diffuse gliomas without IDH1/2 mutations than those with IDH1/2 mutations (36.8% vs 13.6%; P=0.018, 16.7% vs 1.0%; P=0.028, 24.3% vs 8.3%; P=0.006, respectively). PDGFRA gain was most frequent (28.6%) in gliomas lacking any of common genetic alterations (IDH1/2 mutations, TP53 mutations and 1p/19q loss). PDGFRA gain was found in low-grade diffuse gliomas with TP53 mutation ± IDH1/2 mutations (16.3%) and those with IDH1/2 mutation only (10.5%), but rare in tumors with 1p/19q loss ± IDH1/2 mutations (1.4%).
In diffuse astrocytomas, PDGFRA gain positively correlated with MET gain (P=0.016) and inversely correlated with 1p/19q loss (P=0.005) and IDH1/2 mutations (P=0.018). The vast majority of diffuse astrocytomas showed IDH1/2 mutations and/or PDGFRA gain (154/166; 93%).
Mean survival of diffuse astrocytoma patients with PDGFRA gain was 8.8 ± 1.6 years, similar to that with IDH1/2 mutations (7.8 ± 0.5 years) or TP53 mutations (7.6 ± 0.6 years), but significantly longer than those with MET gain (4.4 ± 0.7 years). The mean survival of diffuse astrocytoma patients with co-gain of MET and PDGFRA was 7.7 ± 2.0 years, which was similar to those with PDGFRA gain only.
Dual-color FISH in 6 diffuse astrocytomas with PDGFRA / MET co-gain identified by quantitative PCR revealed PDGFRA and MET were typically amplified in different tumor cell populations within the tumor, but tumor cells with co-amplification were also focally observed, suggesting intra-tumoral heterogeneity even in diffuse astrocytomas.
Citation Format: Kazuya Motomura, Michel Mittelbronn, Werner Paulus, Benjamin Brokinkel, Kathy Keyvani, Ulrich Sure, Karsten Wrede, Yoichi Nakazato, Yuko Tanaka, Naosuke Nonoguchi, Daniela Pierscianek, Young-Ho Kim, Luigi Mariani, Anne Vital, Arie Perry, Hiroko Ohgaki. Intra-tumoral heterogeneity of PDGFRA / MET gain in WHO grade II diffuse astrocytomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2406. doi:10.1158/1538-7445.AM2013-2406