Genetic Alterations In Gliosarcoma And Giant Cell Glioblastoma

Ji Eun OH, International Agency for Research on Cancer, France
OHTA T. 1,2 , NONOGUCHI N. 1,3 , SATOMI K. 1 , CAPPER D. 4 , PIERSCIANEK D. 1,5 , SURE U. 5 , VITAL A. 6 , PAULUS W. 7 , MITTELBRONN M. 8 , ANTONELLI M. 9 , KLEIHUES P. 10 , GIANGASPERO F. 9 , OHGAKI H. 1

1 Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France
2 Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan
3 Department of Neurosurgery, Osaka Medical College, Takatsuki, Japan
4 Department of Neuropathology, German Cancer Research Center, Heidelberg, Germany
5 Department of Neurosurgery, University Hospital Essen, Essen, Germany
6 Bordeaux Institute of Neuroscience, Bordeaux, France
7 Institute of Neuropathology, University Hospital Münster, Münster, Germany
8 Institute of Neurology (Edinger Institute), Goethe-University, Frankfurt/Main, Germany
9 Department of Radiology, Oncology and Anatomic Pathology, Sapienza University of Rome, Rome, Italy
10 Medical Faculty, University of Zurich, Zurich, Switzerland

Purpose
The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. Clinically, they are considered variants of primary glioblastoma, but genetic data are still scant. The objectives of the present study were to further genetically characterize these glioblastoma variants.
Methods
Sanger sequencing was performed for the IDH1/2 mutations and TERT promoter mutations in 36 gliosarcomas and 19 giant cell glioblastomas. Quantitative PCR was performed to assess LOH 1p, 19q, and 10q in 17 gliosarcomas and 12 giant cell glioblastomas. The Illumina Infinium HumanMethylation450 (450k) array was used for 5 gliosarcomas, and chromosomal copy-number profiling was generated using DNA methylation data. ATRX immunohistochemistry was performed on 17 gliosaromas and on 16 giant cell glioblastomas.
Results
IDH1/2 mutations were absent in all 36 gliosarcomas and in 18/19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy-number profiling using the 450k methylome array revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas.
Conclusions
These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastomas occupy a hybrid position between primary and secondary glioblastomas.
Funding sources                                                                         
This project is funded by the International Agency for Research on Cancer and Goethe-University, Frankfurt, Germany.