<i>IGF2</i>/<i>H19</i> imprinting analysis of human germ cell tumors (GCTs) using the methylation‐sensitive single‐nucleotide primer extension method reflects the origin of GCTs in different stages of primordial germ cell development

Sievers, Sonja; Alemazkour, Katayoun; Zahn, Susanne; Perlman, Elizabeth J.; Gillis, Ad J. M.; Looijenga, Leendert H. J.; Göbel, U.; Schneider, Dominik T.

doi:10.1002/gcc.20237

Cited by 84 publications

(93 citation statements)

References 37 publications

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“…This assumption is supported by imprinting studies implicating a common precursor cell for both gonadal and extragonadal germ cell tumors. 5,6 However, there are several lines of evidence that suggest certain biologic differences between central nervous system and non-CNS-GCTs. Testicular germ cell tumors show a characteristic association with a preinvasive carcinoma in situ, the testicular intratubular neoplasia.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…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 sustained survival of germ cells in an extragonadal environment remain unclear. Furthermore, the molecular mechanisms of the apparent tropism to the pineal gland and suprasellar region in particular have to be elucidated.…”

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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

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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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“…GCTs exhibit hypomethylation of the IGF2-H19 locus, autocrine IGF2 expression is not likely to contribute significantly to the growth of these tumors [36][37][38]. Investigations into the imprinting of other loci such as DLK1-MEG3 are lacking in GCTs such as EC, and these studies may prove important considering the epigenome dynamics of the primordial germ cells (PGCs) from which these tumors likely originate [36].…”

Section: The Igf2-h19 and Dlk1-meg3 Loci In Embryogenesis And Malignancymentioning

confidence: 99%

“…Investigations into the imprinting of other loci such as DLK1-MEG3 are lacking in GCTs such as EC, and these studies may prove important considering the epigenome dynamics of the primordial germ cells (PGCs) from which these tumors likely originate [36].…”

Section: The Igf2-h19 and Dlk1-meg3 Loci In Embryogenesis And Malignancymentioning

confidence: 99%

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

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Methylation profiling in individuals with Russell–Silver syndrome

Peñaherrera

Weindler

Allen

et al. 2010

American J of Med Genetics Pt A

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Russell-Silver syndrome (RSS) is a heterogeneous disorder associated with pre- and post-natal growth restriction and relative macrocephaly. Involvement of imprinted genes on both chromosome 7 and 11p15.5 has been reported. To further characterize the role of epimutations in RSS we evaluated the methylation status at both 11p15.5 imprinting control regions (ICRs): ICR1 associated with H19/IGF2 expression and ICR2 (KvDMR1) associated with CDKN1C expression in a series of 35 patients with RSS. We also evaluated methylation at the promoter regions of other imprinted genes involved in growth such as PLAGL1 (6q24), GCE (7q21), and PEG10 (7q21) in this series of 35 patients with RSS. Thirteen of the 35 patient samples, but none of 22 controls, showed methylation levels at ICR1 that were more than 2 SD below the mean for controls. Three RSS patients were highly methylated at the SCGE promoter, all of which were diagnosed with upd(7)mat. To identify further potential global methylation changes in RSS patients, a subset of 22 patients were evaluated at 1505 CpG sites by the Illumina GoldenGate methylation array. Among the few CpG sites displaying a significant difference between RSS patients and controls, was a CpG associated with the H19 promoter. No other sites associated with known imprinted genes were identified as abnormally methylated in RSS patients by this approach. While the association of hypomethylation of the H19/IGF2 ICR1 is clear, the continuous distribution of methylation values among the patients and controls complicates the establishment of clear cut-offs for clinical diagnosis.

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IGF2/H19 imprinting analysis of human germ cell tumors (GCTs) using the methylation‐sensitive single‐nucleotide primer extension method reflects the origin of GCTs in different stages of primordial germ cell development

Cited by 84 publications

References 37 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

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

Methylation profiling in individuals with Russell–Silver syndrome

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