Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization

Abstract

The limited information available to date regarding the genetic alterations in germ cell tumors of the central nervous system has raised concerns about their biologic relationship to other germ cell tumor entities. We investigated fresh-frozen or archival tumor samples from 19 patients with central nervous system germ cell tumors (CNS-GCTs), including seven germinomas, eight malignant nongerminomatous germ cell tumors and four teratomas, using chromosomal comparative genomic hybridization to determine recurrent chromosomal imbalances. All 15 malignant CNS-GCTs and two of four teratomas showed multiple chromosomal imbalances. Chromosomal gains (median: 4 gains/tumor, range: 0-9 gains/tumor) were observed more frequently than losses (median: 1.6 losses/tumor, range: 0-6 losses/tumor). Gain of 12p, which is considered characteristic for germ cell tumors of the adult testis, was detected in 11 of 19 tumors and 10 of 15 malignant CNS-GCTs. In one tumor, gain of 12p was confined to an amplicon at 12p12, corresponding to the commonly amplified region on 12p. Other common gains were found on chromosome arms 1q and 8q (n ¼ 9, each). Among the chromosomal losses, parts of chromosome 11 (n ¼ 5), 18 (n ¼ 4), and 13 (n ¼ 3) were deleted most frequently. Notably, we observed no difference in the genetic profiles of germinomatous and nongerminomatous CNS-GCTs; however, the average number of imbalances was higher in the latter group. A meta-analysis comparing 116 malignant gonadal and extragonadal germ cell tumors revealed that the genomic alterations in CNS-GCTs are virtually indistinguishable from those found in their gonadal or other extragonadal counterparts of the corresponding age group. These data strongly argue in favor of common pathogenetic mechanisms in gonadal and extragonadal germ cell tumors. Keywords: germ cell tumor; central nervous system; extragonadal; chromosomal profile; isochromosome 12p; meta-analysis During childhood and adolescence, the majority of germ cell tumors arise outside of the gonads, and beyond early childhood, the central nervous system and the mediastinum constitute the most frequent sites of extragonadal germ cell tumors. 1 The vast majority of central nervous system germ cell tumors (CNS-GCTs) develop in the pineal gland or the suprasellar region, and approximately 10% of all CNS-GCTs present as bifocal tumors. 2,3 The extragonadal appearance of germ cell tumors is likely related to errors in germ cell migration during early embryonal development. Accordingly, imprinting studies of gonadal and extragonadal germ cell tumors show loss of the methylation imprint at imprinting control regions, correlating with the methylation status within early stages of primordial germ cell development. [4][5][6] However, the molecular mechanisms that interfere with normal homing of germ cells to the gonadal ridge and that allow for a

Malignant germ cell tumours of childhood: new associations of genomic imbalance

“…In a complimentary manner, the typical cytogenetic changes of YSTs in infants (loss on 1p, 4q and 6q) were also seen in YSTs of children over 5 years (always ovarian in this study), but with a reduced frequency. This is in keeping with published findings in pure histology YSTs affecting adolescents and adults, irrespective of tumour site (Speleman et al, 1990;de Bruin et al, 1994;Korn et al, 1996;Mostert et al, 1996;van Echten et al, 1996;Riopel et al, 1998;Summersgill et al, 1998;Kraggerud et al, 2000;Schneider et al, 2006). These findings suggest that whereas biological differences may exist between MGCTs of similar histology, distinction based simply on chronological age may not be appropriate.…”

“…Particular histologies are reported to show similar patterns of genomic imbalance irrespective of the site in which they occur (Riopel et al, 1998;Perlman et al, 2000;Rickert et al, 2000;Schneider et al, 2002;Schneider et al, 2006), consistent with the hypothesis that they arise from the same progenitor cell. Recently, a new classification system for GCTs was proposed (Oosterhuis and Looijenga, 2005), dividing GCTs into five types.…”

“…There have been several investigations of small numbers of cases, generally as a component of studies that also included teratomas. A wide range of CNIs has been described in childhood MGCTs, including gains on 1q, 2p, 3, 7, 8, 13, 14, 20q, 21, and X, as well as losses on 1p36, 4q, 6q, 11, 13 and 18; but again none is seen consistently Perlman et al, 2000;Schneider et al, 2002;van Echten et al, 2002;Schneider et al, 2006). In all these studies, comparative genomic hybridisation (CGH) findings were consistent with previous cytogenetic data and with verification studies based on fluorescent in situ hybridisation.…”

Common molecularcytogenetic alterations in tumors originating from the pineal region

“…Cytogenetic analysis of cerebral GCT, particularly GCT of the PR, are seldom reported, with 27 pineal GCTs reported to date (28,29). In these studies, the gain of 12p, a hallmark in testicular GCT (30), was detected at varying frequencies.…”

Mixed Malignant Germ Cell Tumour of Third Ventricle with Hydrocephalus: A Rare Case with Recurrence

“…Individuals with Klinefelter syndrome, Down syndrome & with neurofibromatosis type 1 are prone to develop intracranial GCTs [10,11].…”