PDGFRA Amplification is Common in Pediatric and Adult High-Grade Astrocytomas and Identifies a Poor Prognostic Group in IDH1 Mutant Glioblastoma

• Authors: Joanna J. Phillips, University of California San Francisco; Derick Aranda, University of California San Francisco; David W. Ellison, St. Jude Children’s Research Hospital; Alexander R. Judkins, St. Jude Children’s Research Hospital; Sidney E. Croul, University of Toronto; Daniel J Brat, Emory University; Keith L. Ligon, Dana Farber Cancer Institute; Craig Horbinski, University of Kentucky; Sriram Venneti, Memorial Sloan-Kettering Cancer Center; Gelareh Zadeh, University of Toronto; Mariarita Santi, Childrens Hospital of Philadelphia; Shengmei Zhou, Childrens Hosp Los Angeles; Christina L. Appin, Emory University; Stefano Sioletic, Brigham and Women’s Hospital and Harvard Medical School; Lisa M. Sullivan, Childrens Hospital of Philadelphia; Maria Martinez-Lage, University of Pennsylvania Health System,; Aaron E. Robinson, University of California San Francisco; William H. Yong, University of California Los Angeles; Timothy Cloughesy, University of California Los Angeles; Albert Lai, University of California Los Angeles; Heidi S. Phillips, Genentech Inc; Roxanne Marshall, University of California San Francisco
• Journal Title: Brain Pathology
• Volume: Volume 23, Number 5
• Publisher: Wiley | 2013-09-01, Pages 565-573
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/bpa.12043
• Subjects: Health Sciences, Pathology; Biology, Neuroscience
• Keywords: Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; Neurosciences; Pathology; Neurosciences & Neurology; astrocytoma; FISH; IDH1; isocitrate dehydrogenase 1; PDGFRA; prognosis; INTEGRATED GENOMIC ANALYSIS; GROWTH-FACTOR; DIFFUSE GLIOMAS; EGFR; CELL; EXPRESSION; SUBCLASSES; AUTOCRINE; MUTATIONS; RECEPTORS

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.