Comparative genomic hybridization of germ cell tumors of the adult testis: Confirmation of karyotypic findings and identification of a 12p-amplicon

Mostert, Marijke; Pol, Marjolein van de; Weghuis, D.E.M. Olde; Suijkerbuijk, Ron F.; Kessel, A.H.M. Geurts van; Echten, Jannie van; Oosterhuis, J. Wolter; Looijenga, Leendert

doi:10.1016/0165-4608(96)00043-x

Cited by 96 publications

(88 citation statements)

References 26 publications

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“…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-gctssupporting

confidence: 67%

“…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gonadal and extragonadal GCTs, separated by age and sorted by site 14,17,18,29,34 (including this series and 16 unpublished tumors).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: 61%

“…In accordance with this hypothesis, Rickert et al detected no chromosomal imbalances in two of eight germinomas, whereas in our series, all malignant tumors showed genomic alterations. Furthermore, it might be argued whether the high-resolution CGH algorithm might additionally increase the hetero- Figure 4 Meta-analysis of 36 testicular and 34 CNS-GCTs, separated by site and sorted by age 15,18,34 (including this series and eight unpublished tumors).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: The Role Of Gain Of 12p In Cns-gctsmentioning

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: The Role Of Gain Of 12p In Cns-gctssupporting

confidence: 67%

Section: Discussionmentioning

confidence: 61%

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

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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“…We have recently cloned a novel growth inhibitor and candidate tumour suppressor gene called ING1 using a method that combined PCR-mediated subtractive hybridization of cDNAs (Lisitsyn et al, 1993) from normal and cancerous cells with adaptor-mediated enrichment (Diatchenko et al, 1996) and an in vivo selection assay (Garkavtsev et al, 1996). The ING1 gene localized to chromosome 13q33 ± 34 (Garkavtsev et al, 1997b), a site that has been implicated in the progression of various tumours (Maestro et al, 1996;Motomura et al, 1988;Mostert et al, 1996;YangFeng et al, 1992). It also appears to have a role in programmed cell death as its expression confers sensitivity to apoptosis whereas antisense ING1 protects cells from apoptosis in di erent experimental systems (Helbing et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Suppression of ING1 expression in sporadic breast cancer

et al. 1999

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Down regulation of the ING1 candidate tumour suppressor promotes growth in soft agar and focus formation in vitro and tumour formation in vivo. ING1 encodes a nuclear, cell cycle-regulated protein, overexpression of which e ciently blocks cell growth and is capable of inducing apoptosis in di erent experimental systems. Here we present the ®rst report of ING1 mutation and expression analysis in a total of 452 cancer samples. One germline missense alteration and three germline silent alterations were detected in 377 primary breast cancers while marked (2 ± 10-fold) decreases in ING1 mRNA expression were seen in 44% of primary breast cancers and in ten of ten breast cancer cell lines examined. Furthermore, the majority of breast cancers (58%) showing decreased ING1 expression had metastasized to regional lymph nodes whereas only 9% of cancers with elevated ING1 expression, compared to adjacent normal tissues, were metastatic. Thus, ING1 mutation is very rare in breast or ovarian cancers, however, repression of ING1 expression frequently accompanies tumour development of breast cancer.

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“…Cytogenetic, comparative genomic hybridisation (CGH) and allelic imbalance studies of SE and NS have shown that a number of regions in addition to 12p are imbalanced. Reported frequent aberrations common to both SE and NS include gain of material from chromosomes 1, 7, 8, 17, 21 and X and loss of material from chromosomes 4, 5, 11, 13, 18 and Y (van Echten et al, 1995;Korn et al, 1996;Mostert et al, 1996;Sandberg et al, 1996;Summersgill et al, 1998a, b;Kraggerud et al, 2002;von Eyben et al, 2004). In recent years, a number of expression profiling studies have been reported and these have identified overexpressed genes and expression signatures, which distinguish different subtypes of NS (Skotheim et al, 2005).…”

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confidence: 99%

Genomic copy number and expression patterns in testicular germ cell tumours

McIntyre

Summersgill

et al. 2007

Br J Cancer

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Testicular germ cell tumours of adults and adolescents (TGCT) include seminomas (SE) and nonseminomas (NS), with spermatocytic seminomas (SSE) representing a distinct entity in older men. SE and NS have gain of 12p material in all cases, whereas SSE are associated with overrepresentation of chromosome 9. Here, we compare at the chromosomal level, copy number imbalances with global expression changes, identified by comparative expressed sequence hybridisation analyses, in seven SE, one combined tumour, seven NS and seven cell lines. Positive correlations were found consistent with copy number as a main driver of expression change, despite reported differences in methylation status in SE and NS. Analysis of chromosomal copy number and expression data could not distinguish between SE and NS, in-keeping with a similar genetic pathogenesis. However, increased expression from 4q22, 5q23.2 and 9p21 distinguished SSE from SE and NS and decreased copy number and expression from 2q36 -q37 and 6q24 was a specific feature of NS-derived cell lines. Our analysis also highlights 19 regions with both copy number and expression imbalances in greater than 40% of cases. Mining available expression array data identified genes from these regions as candidates for involvement in TGCT development. Supplementary data is available at

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Comparative genomic hybridization of germ cell tumors of the adult testis: Confirmation of karyotypic findings and identification of a 12p-amplicon

Cited by 96 publications

References 26 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

Suppression of ING1 expression in sporadic breast cancer

Genomic copy number and expression patterns in testicular germ cell tumours

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