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Malignant and benign ganglioglioma: A pathological and molecular study¹

Arthur & Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario (A.P., A.B., A.G.); and Divisions of Neurosurgery (R.P., A.G.) and Neuropathology (P.S.), University Health Network, Toronto, Ontario; Canada

² Address Correspondence to Abhijit Guha, M.D., FRCSC, 4W-446 Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8 (Abhijit.Guha{at}uhn.on.ca).

Gangliogliomas are generally benign tumors, composed of transformed neuronal and glial elements, with rare malignant progression of the glial component. The current study of a rare case of a woman harboring a ganglioglioma with areas of malignant transformation addresses two fundamental questions: (1) Are the ganglioglioma and its malignant component clonal in origin? (2) What are the genetic alterations associated with the initiation and subsequent malignant progression of ganglioglioma? By using the human androgen receptor gene (HUMARA) assay, we found the ganglioglioma and the malignant component to be clonal in origin, suggestive of initial transformation of a single neuroglial precursor cell with subsequent malignant progression. Conventional and array comparative genomic hybridization (approximately 2.5-Mb resolution) analyses found chromosomal losses to be predominant in the benign areas of the ganglioglioma, with gains more prevalent in the malignant component. Regions of chromosomal loss, postulated to harbor genes involved in the initiation of ganglioglioma, included 1p35-36, 2p16-15, 3q13.1-13.3, 3q24-25.3, 6p21.3-21.2, 6q24-25.2, 9p12, Xp11.3-11.22, and Xq22.1-22.3. Direct analysis demonstrated loss of p19 expression and p53 mutation in the malignant areas, highly suggestive of these alterations being involved in the malignant progression of the ganglioglioma. Additional chromosomal alterations specific to the malignancy involved gains on 1p35-34.2, 2q24.1-32.3, 3q13.1-13.3, 6q13-16.2, 7q11.2-31.3, 8q21.1-23, 11q12-31, and 12q13.2-21.3. This molecular-pathological study has provided insight into the pathogenesis of gangliogliomas and associated rare malignant progression. Deciphering the specific genes residing in these chromosomal regions may further our understanding of not only these rare tumors but also the more common gliomas.

Key Words: array CGH (aCGH) • comparative genomic hybridization (CGH) • ganglioglioma • human androgen receptor gene (HUMARA) • malignant ganglioglioma

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