Testicular germ-cell tumours in a broader perspective

Oosterhuis, J. Wolter; Looijenga, Leendert H. J.

doi:10.1038/nrc1568

Cited by 829 publications

(1,006 citation statements)

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“…Testicular germ cell tumors show a characteristic association with a preinvasive carcinoma in situ, the testicular intratubular neoplasia. 7,31,42 No such in situ lesion has been seen in the brain of patients with CNS-GCT. Furthermore, it has been demonstrated that certain histologic types express markers associated with distinct maturational stages of germ cell development, which presumably are dependent on a specific gonadal environment.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it has been demonstrated that certain histologic types express markers associated with distinct maturational stages of germ cell development, which presumably are dependent on a specific gonadal environment. 7,[43][44][45] Lastly, there are some data suggesting that the chromosomal marker characteristic of testicular germ cell tumors, the isochromosome 12p, plays only a minor role in CNS-GCTs. 18,22 As a consequence, it must be debated whether the information generated in the more frequent (and more easily assessable) testicular germ cell tumors can indeed be transferred to CNS-GCTs without scrutiny.…”

Section: Discussionmentioning

confidence: 99%

“…These are characterized by a specific cytogenetic aberration, the isochromosome 12p (i (12p)), which is considered pathognomonic and can be detected in about 80% of malignant testicular germ cell tumors. 7 In the remaining tumors, gain of chromosomal material of 12p is related to either marker chromosomes or homogeneously staining regions that contain chromosomal material derived from chromosomal band 12p11.2-12.1. 8,9 Additional chromosomal imbalances have also been reported in testicular germ cell tumors.…”

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confidence: 99%

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

et al. 2006

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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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2006

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“…A somatic type of imprint, however, is erased by demethylation, while these cells migrate toward the genital ridges ϳ 10.5 dpc (Lee et al, 2002). The erasing of the methylation (imprint) of H19, Igf-2, Igf-2R, and Snrpn in early PGC could be envisioned as one of the mechanisms that shuts down PGC developmental pluripotency and makes these cells resistant to potential parthenogenesis or formation of teratomas (Macchiarini and Ostertag, 2004;Oosterhuis and Looijenga, 2005). A proper somatic imprint is subsequently again reestablished in sperm and oocytes, so that a fertilized egg expresses a developmentally proper somatic imprint of these crucial genes.…”

Section: Regulation Of Pluripotency In the Germ Line By Status Of Sommentioning

confidence: 99%

Bone marrow‐derived very small embryonic‐like stem cells: Their developmental origin and biological significance

Kucia

Wan

Ratajczak

2007

Developmental Dynamics

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Data from our and other laboratories provide evidence that bone marrow (BM) contains a population of stem cells that expresses early developmental markers such as (1) stage-specific embryonic antigen (SSEA) and (2) transcription factors Oct-4 and Nanog. These are the markers characteristic for embryonic stem cells, epiblast stem cells, and primordial germ cells (PGC). The presence of these stem cells in adult BM supports the concept that this organ contains some population of pluripotent stem cells that is deposited in embryogenesis during early gastrulation. We hypothesize that these cells could be direct descendants of the germ lineage that, to pass genes on to the next generations, has to create soma and, thus, becomes a "mother lineage" for all somatic cell lineages present in the adult body. Germ potential is established after conception in totipotent zygotes and retained in blastomeres of morula, cells from the inner cell mass of blastocyst, epiblast, and population of PGC. We will present a concept that SSEA ؉ Oct-4 ؉ Nanog ؉ cells identified in BM could be descendants of epiblast cells as well as some rare migrating astray PGC. Developmental Dynamics 236:3309 -3320, 2007.

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“…In particular, seminoma cells mimic early germ cells, probably PGCs or gonocytes (Skakkebaek et al, 1987). Recent immunohistochemical data demonstrated that seminoma and embryonal carcinoma cells are positive for OCT3/4, suggesting TGCTs derive from PGCs (Looijenga et al, 2003;Rajpert-De Meyts et al, 2004;Oosterhuis and Looijenga, 2005).…”

Section: Introductionmentioning

confidence: 99%

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

et al. 2006

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Genome-wide epigenetic modification plays a crucial role in regulating genome functions at critical stages of development. In particular, DNA methylation is known to be reprogrammed on a genome-wide level in germ cells and in preimplantation embryos, although it is relatively stable in somatic cells. In this reprogramming process, the genome becomes demethylated, and methylated de novo during later stages of development. Reprogramming of DNA methylation in male germ cells has not been fully investigated. Testicular germ cell tumors (TGCTs) possess a pluripotential nature and display protean histology from germ cells to embryonal and somatic cell differentiation. These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming. In order to obtain an insight into the epigenetic dynamics of TGCTs, we conducted a comprehensive analysis of differential methylated regions (DMRs) on H19 and IGF2 in TGCTs compared with testicular malignant lymphomas. In the present study, we show that methylation imprint at the promoter and CTCF-binding site upstream of H19 was completely erased in both seiminomatous and nonseminomatous TGCTs, whereas differential methylation was observed in testicular lymphomas. The erasure of methylation imprint was also observed in TGCTs with malignant transformation. We found biallelic unmethylation at the promoter and the CTCF-binding site upstream of H19 is required, but not sufficient for the biallelic expression of H19 in TGCTs. These data suggest that factors other than methylation contribute to transcriptional regulation of imprinted genes in TGCTs. The present data have shown that TGCTs carry distinctive epigenetic profiles at the core-imprinting domain of H19/ IGF2 from other neoplasms of somatic cell origin. The data also suggest that both seminomatous and nonseminomatous TGCTs carry methylation profiles similar to fetal germ cells, but not adult germ cells, indicating the origin of TGCTs as fetal germ cells.

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Testicular germ-cell tumours in a broader perspective

Cited by 829 publications

References 151 publications

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

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

Bone marrow‐derived very small embryonic‐like stem cells: Their developmental origin and biological significance

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

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