Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents

Schneider, Dominik T.; Schuster, Amy E.; Fritsch, Michael K.; Calaminus, Gabriele; Göbel, U.; Harms, D.; Lauer, Stephen J.; Olson, Thomas A.; Perlman, Elizabeth J.

doi:10.1002/gcc.10053

Cited by 101 publications

(100 citation statements)

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“…Furthermore, the additional chromosomal imbalances such as gain of 1q or 8 also occur at comparable frequencies as in other gonadal and nongonadal germ cell tumors of adults (Figures 3 and 4). Although CNS-GCTs show no bimodal age distribution as testicular or mediastinal germ cell tumors, 1 our analysis suggests that also in the CNS, germ cell tumors of infancy and early childhood are genetically distinct from those of adolescence and adulthood, as indicated by the analysis of patients 1 and 12, which show profiles characteristic of teratoma and malignant germ cell tumors of Figure 3 Meta-analysis of 116 malignant gonadal and extragonadal GCTs, separated by age and sorted by site 14,17,18,29,34 (including this series and 16 unpublished tumors). Each line represents 100 chromosomal data points of a single tumor, with chromosomal gains illustrated as green bars and losses as red bars, respectively.…”

Section: Discussionmentioning

confidence: 67%

“…Characteristically, the vast majority of teratomas indeed do not show chromosomal aberrations on cytogenetic, CGH or array CGH analyses. 13,16,17,47 Nevertheless, it is very important to note that two of the teratomas included in our study (and both immature central nervous system teratomas analyzed by Rickert et al) show chromosomal imbalances resembling those of malignant germ cell tumors. This might indicate that in contrast to teratomas in infants, teratomas of adolescents and adults might be related to a maturational differentiation of malignant germ cell tumors with a preservation of genetic aberrations that may result in a potentially malignant clinical presentation (accordingly, patient no.…”

Section: The Role Of Gain Of 12p In Cns-gctsmentioning

confidence: 66%

“…The Figures 3 and 4 illustrate that this frequency is almost identical to that found in testicular 11,34 and mediastinal germ cell tumors of adolescents and adults. 17 In addition, our meta-analysis underlines that CNS-GCTs without 12p gain do not show chromosomal patterns distinct from other germ cell tumors.…”

Section: The Role Of Gain Of 12p In Cns-gctsmentioning

confidence: 77%

“…Tumor and reference DNA (2 mg) were directly labeled with Spectrum-Green-and Spectrum-Red-dUTP (Vysis, Downers Grove, IL, USA) using nick translation, as previously described. 14,17,29 The amount of DNase and DNA-Polymerase (GibcoBRL) and the reaction time were carefully adjusted in order to obtain labeled DNA fragment lengths of 500-2000 base pairs on a 1% agarose gel.…”

Section: Labeling Of Tumor and Reference Dnamentioning

confidence: 99%

“…[13][14][15][16] In extragonadal germ cell tumors, similar age-dependent cytogenetic and moleculargenetic patterns have been identified. 13,17 There are only limited data regarding cytogenetic and molecular genetic patterns of intracranial germ cell tumors. The largest genetic study published to date includes 15 pineal germ cell tumors analyzed with comparative genomic hybridization (CGH).…”

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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: 67%

Section: The Role Of Gain Of 12p In Cns-gctsmentioning

confidence: 66%

Section: The Role Of Gain Of 12p In Cns-gctsmentioning

confidence: 77%

Section: Labeling Of Tumor and Reference Dnamentioning

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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Klinefelter syndrome and mediastinal germ cell tumors

Völkl

Langer

Aigner

et al. 2006

American J of Med Genetics Pt A

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an 8.5-year-old boy presented with signs of precocious puberty. Laboratory analyses (suppressed gonadotropins, elevated testosterone) and thoracic CT demonstrated a beta-human chorionic gonadotropin (beta-hCG) and alpha(1)-feto protein (alpha-FP) secreting mediastinal tumor. Histological analysis showed a mixed germ cell tumor comprising choriocarcinoma (CH), embryonal carcinoma (EC), mature teratoma (MT), and yolk sac tumor (YS). He was successfully treated by surgery and adjuvant chemotherapy. Epianalysis of published cases: all KS patients (n = 12), age 4-9 years, presented with precocious sexual development (PP), whereas the older ones showed thorax-associated symptoms, mainly chest pain, dyspnea, and cough. The histological distribution was also age-dependent with mixed germ cell tumors predominantly in younger patients. Thus, M-GCTs are strongly associated with precocious puberty in young boys with KS. Therefore, a karyotype analysis should be included in the clinical work-up of boys with precocious puberty and M-GCT. There is still no convincing explanation for the association of M-GCTs and KS.

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Klinefelter syndrome in males with germ cell tumors: A report from the Children's Oncology Group

Williams

Pankratz

Lane

et al. 2018

Cancer

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Background Males with Klinefelter syndrome (KS; 47, XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. There are no reports characterizing the prevalence of KS among male GCT cases. Methods We used array genotyping data from a Children’s Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (n=433; aged 0–19 years). Using Fisher’s exact tests, we examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and a number of birth characteristics between KS-GCT cases and GCT cases without chromosomal abnormalities. Using publicly available data, we estimated the 1-year risk, risk ratio (RR), and corresponding 95% confidence interval (95% CI) of GCTs among KS cases. Results Based on analysis of array genotyping data, 3% (n=13) of male GCT cases had KS. The additional X chromosome was of maternal origin in7/13 cases. Of these 13 KS cases, 5/9 (56%) KS-GCT cases with parental questionnaire data reported a diagnosis of KS. We did not observe significant differences in patient or birth characteristics between KS-GCT and non-KS-GCT cases. KS-GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non-KS-GCT cases (p<0.01). We estimated the risk of developing a GCT among males with KS to be 0.00025, or 1/4,000 (RR: 18.8; 95% CI: 11.7, 30.0). Conclusions Compared to males without chromosomal abnormalities, KS males are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT.

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Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents

Cited by 101 publications

References 41 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

Klinefelter syndrome and mediastinal germ cell tumors

Klinefelter syndrome in males with germ cell tumors: A report from the Children's Oncology Group

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