Detection of chromosomal DNA gains and losses in testicular germ cell tumors by comparative genomic hybridization

Korn, W. Michael; Weghuis, D.E.M. Olde; Suijkerbuijk, Ron F.; Schmidt, Ulrich; Otto, Thomas D.; Manoir, Stanislas du; Kessel, Ad Geurts van; Harstrick, A.; Seeber, S.; Becher, R.

doi:10.1002/(sici)1098-2264(199610)17:2<78::aid-gcc2>3.0.co;2-y

Cited by 86 publications

(62 citation statements)

References 26 publications

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“…This probe showed between 15 ± 30 hybridization signals per nucleus in these tumors as reported before in other TGCTs (Suijkerbuijk et al, 1994;Mostert et al, 1996b;Korn et al, 1996). Circumstantial evidence that YAC#5 indeed maps within (or at least close to) the critically ampli®ed region was obtained by combining CGH on tumor T2207 with FISH of YAC#5: YAC#5 hybridization co-incided exactly with the ampli®ed 12p-region, both in metaphase spreads and interphase nuclei (not shown).…”

Section: Detection Of 12p-ampli®cationsupporting

confidence: 78%

“…One possible strategy was initiated by our previous identi®cation of a metastatic SE showing ampli®cation of a restricted region of 12p (Suijkerbuijk et al, 1994). More recently, we and others demonstrated via comparative genomic hybridization (CGH), a technique developed to identify relative (sub-) chromosomal gains and losses (Kallioniemi et al, 1992), that also a certain percentage of primary TGCTs shows ampli®cation of a restricted region of 12p, cytogenetically similar to the one observed before (Mostert et al, 1996a;Korn et al, 1996). This ®nding of a restricted 12p-ampli®cation allows identi®cation of relevant genes using a direct approach.…”

Section: Introductionmentioning

confidence: 99%

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Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

et al. 1998

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Cytogenetically, testicular germ cell tumors of adolescents and adults (TGCTs) are characterized by gain of 12p-sequences, most often through isochromosome formation (i(12p)). Fluorescence in situ hybridization (FISH) has shown that i(12p))-negative TGCTs also cryptically contain extra 12p-sequences. The consistency of 12p-over-representation in all histological subtypes of TGCTs, including their preinvasive stage, suggests that gain of one or more genes on 12p is crucial in the development of this cancer. So far, studies aimed at the identi®cation of the relevant gene(s) were based on thè candidate-gene approach'. No convincing evidence in favor of or against a particular gene has been reported. We combined conventional karyotyping, comparative genomic hybridization, and FISH to identify TGCTs with ampli®cations of restricted regions of 12p. Out of 49 primary TGCTs (23 without i(12p), 13 with and 13 unknown), eight tumors (six without i(12p) and two unknown) showed ampli®cations corresponding to 12p11.1-p12.1. Using bicolour-FISH, physical mapping, and semi-quantitative polymerase chain reactions, the size of the shortest region of overlap of ampli®cation (SROA) was estimated to be between 1750 ± 3000 kb. In addition, we mapped a number of genes in and around this region. While fourteen known genes could be excluded as candidates based on their location outside this region, we demonstrate that KRAS2, JAW1 and SOX5 genes are localized within the SROA. While KRAS2 and JAW1 map to the proximal border of the SROA, SOX5 maps centrally in the SROA. KRAS2 and JAW1 are expressed in all TGCTs, whereas one 12p amplicon-positive TGCT lacks expression of SOX5. The critical region of 12p over-represented in TGCTs is less than 8% of the total length of the short arm of chromosome 12. It will be helpful in the identi®cation of the gene(s) involved in TGCT-development.

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Section: Detection Of 12p-ampli®cationsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

et al. 1998

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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%

“…However, these are less frequent and less consistent as compared to gain of 12p. [10][11][12] Notably, testicular germ cell tumors that arise during infancy and childhood show a divergent genetic profile that is characterized by loss of 1p and 6q, and gain of 1q and 20, while gain of 12p11-12 is not detectable. [13][14][15][16] In extragonadal germ cell tumors, similar age-dependent cytogenetic and moleculargenetic patterns have been identified.…”

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confidence: 99%

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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“…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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Detection of chromosomal DNA gains and losses in testicular germ cell tumors by comparative genomic hybridization

Cited by 86 publications

References 26 publications

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

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

Genomic copy number and expression patterns in testicular germ cell tumours

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