Genome-wide survey for chromosomal imbalances in ganglioglioma using comparative genomic hybridization

Abstract

Ganglioglioma is a mixed neuronal and glial tumor first described by Perkin in 1926. Because of its rare occurrence in the central nervous system, the pathogenesis of this neoplasm is still largely unknown. Previous studies of ganglioglioma mainly focused on histologic features, immunohistochemical analysis, clinical treatment, and patient outcome. Very few cytogenetic and molecular genetic studies have been reported on this neoplasm. To better understand the mechanism underlying the development of ganglioglioma, we performed comparative genomic hybridization analysis to investigate chromosomal imbalances across the entire genome in five cases of gangliogliomas. Loss of genetic material on the short arm of chromosome 9 was a common genetic alteration found in three of five cases. Overrepresentation of partial or the whole chromosome 7 was another recurrent chromosomal imbalance, confirmed by fluorescence in situ hybridization. Immunohistochemical analysis was performed; all five cases revealed no reaction or low expression for epidermal growth factor receptor antibody. Our study highlights chromosomal regions for further fine mapping and investigation of candidate tumor suppressor genes involved in the pathogenesis of ganglioglioma.

Introduction

Ganglioglioma is a rare, mixed neuronal and glial tumor in the central nervous system (CNS), with an incidence of 0.4–1.3% of all intracranial tumors 1, 2. It usually occurs in children and young adults with a mean age of 8.5–25 years at diagnosis, and patients usually show a favorable biologic behavior and have a good prognosis. Although the most frequent intracranial location of ganglioglioma is the temporal lobe, the tumor may occur in sites throughout the CNS, such as the spinal cord, optic chiasm, and pineal and intraventricular region 3, 4, 5, 6, 7, 8, 9, 10, 11. Histologically, the tumor is characterized by the presence of mature ganglion cells mixed with neoplastic glial cells corresponding to World Health Organization (WHO) grade 1 or 2. The glial component is most commonly a fibrillary astrocytoma, but not infrequently it is a pilocytic astrocytoma 1, 2, 12, 13. However, a high-grade variant is also recognized by the glial component of anaplastic astrocytoma or glioblastoma multiforme (GBM), and the patients who experienced recurrence or malignant transformation were also reported 3, 4, 14, 15, 16, 17, 18, 19. Immunohistochemically, the tumor reveals synaptophysin positivity for ganglion cells and glial fibrillary acidic protein (GFAP) positivity for glial component.

Most of the previous studies on ganglioglioma were involved in histologic features, clinical treatment, patients' outcome, ultrastructural characteristics, and immunohistochemical analysis 3, 4, 13, 16, 17, 20, 21, 22, 23. Approximately 20 cases of gangliogliomas were studied cytogenetically 19, 23, 24, 25, 26, 27. Chromosomal abnormalities were observed in eight of 20 cases studied. Neumann et al. reported an abnormal karyotype in three of 14 gangliogliomas, including a ring chromosome 1; trisomies of chromosomes 5, 6, and 7, and deletion of chromosome 6 [25]. A complex karyotype showing inversion, translocations, and gains or losses of chromosomes 6, 7, 11, 13, 15, 16, 18, 19, and Y was observed in a ganglioglioma with malignant transformation in the study by Jay et al. [27]. Taken together, it seems that gain of chromosome 7 and loss of chromosome 6 are likely to be the common genetic aberrations in these studies. Very few molecular genetic studies were performed on this rare tumor. In Liang et al.'s study, allelic loss on the short arm of chromosome 6 was detected in one of two gangliogliomas [28]. Another study reported that alteration of the tuberous sclerosis 2 gene (TSC2) may play a role in the pathogenesis of sporadic ganglioglioma [29].

Comparative genomic hybridization (CGH) is a molecular cytogenetic technique that allows rapid detection of chromosomal imbalances such as DNA gains or losses across the whole genome 30, 31. To better understand the pathogenesis of ganglioglioma, we performed a genome-wide survey for genetic imbalances in five cases of this neoplasm by using CGH analysis. Chromosomal imbalances were detected in all five tumor samples. Loss of partial chromosome 9p and gain of chromosome 7 were recurrent genetic events found in our series.