Identification of recurrent chromosomal aberrations in germ cell tumors of neonates and infants using genomewide array‐based comparative genomic hybridization

Veltman, Imke M.; Veltman, Joris A.; Janssen, Irene M.; Kaa, Christina Hulsbergen–van de; Oosterhuis, Wolter; Schneider, Dominik; Stoop, Hans; Gillis, Ad J. M.; Zahn, Susanne; Looijenga, Leendert H. J.; Göbel, U.; Kessel, Ad Geurts van

doi:10.1002/gcc.20208

Cited by 38 publications

(22 citation statements)

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“…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%

“…[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. 13,17 There are only limited data regarding cytogenetic and molecular genetic patterns of intracranial germ cell tumors.…”

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confidence: 85%

“…geneity tolerance as it has been postulated for array CGH. 54 In this context, it has to be noted that although the spatial resolution of chromosomal CGH is limited, even with array CGH approaches no discrepant or additional frequently recurrent imbalances have been detected in extracranial germ cell tumors 16 or CNS-GCTs (Chin C Lau, oral presentation on the Second International Symposium in CNS-GCTs in Los Angeles, November 2005 55 ).…”

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-gctsmentioning

confidence: 66%

mentioning

confidence: 85%

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 i12p status at extragonadal sites remains poorly understood. In the largest study of the pediatric population via genome-wide, array-based comparative genomic hybridization, 21 seven out of eight mature sacrococcygeal teratomas and one of two immature sacrococcygeal teratomas showed no cytogenetic aberrations; the two outlier cases were both negative for i12p or gain of 12p. Aside from the above mentioned single case report of mature teratoma with an element of adenocarcinoma, 19 the cytogenetic profile of adult sacrococcygeal teratomas has never been examined.…”

Section: Discussionmentioning

confidence: 99%

Sacrococcygeal teratomas: clinico-pathological characteristics and isochromosome 12p status

et al. 2014

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The biological behavior of teratomas is highly variable, and morphologic features alone are insufficient to predict their clinical course. Prognostic factors that influence behavior include the following: patient sex, age, anatomic site, coincident neoplasm, and cytogenetic abnormalities. Gonadal teratomas have been wellcharacterized; postpubertal testicular teratomas are commonly associated with isochromosome 12p (i12p) and considered to nearly always carry a potential for malignant behavior, whereas ovarian and prepubertal testicular teratomas are i12p negative and predominantly benign in behavior. For extragonadal sites, such as sacrum and coccyx, clinical characteristics and i12p status are yet to be adequately characterized. As part of this study, we identified 19 sacrococcygeal teratomas in our surgical pathology archives from 1990 to 2012. Clinical records and slides were reviewed to confirm the original diagnosis. Gains in chromosome 12p, including i12p status were assessed in representative paraffin sections by fluorescence in situ hybridization. Our cases included 16 mature sacrococcygeal teratomas (11 prepubertal and 5 postpubertal) and three immature saccrococygeal teratomas (all prepubertal). Among mature teratomas, the average tumor size was larger in adults compared with prepubertal patients. A higher number of adult cases were recurrences (80% vs 21%), but only pediatric recurrences were managed with postoperative chemotherapy. All examined tumors were negative for i12p. 100% survival was documented in our cohort with a median follow-up of 6 years. We present a large series of sacrococcygeal teratomas and the first series to examine postpubertal adults at this anatomic site. All tumors lacked chromosome 12p gains, including i12p. Both pre-and postpubertal sacrococcygeal teratomas had a favorable outcome regardless of age or sex.

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“…However, these have a different cell of origin and chromosomal constitution. [8][9][10][11] The precursor lesions of the type-II GCTs have been identified and characterized to a certain extent. The most important observations in the context of DSD will be discussed here.…”

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Tumor risk in disorders of sex development (DSD)

Looijenga¹,

Hersmus²,

Oosterhuis

et al. 2007

Best Practice & Research Clinical Endocrinology & Metab

195

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Disorders of sex development (DSD), previously referred to as intersex disorders, comprise a variety of anomalies defined by congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. Besides issues such as gender assignment, clinical and diagnostic evaluation, surgical and psychosocial management, and sex steroid replacement, the significantly increased risk for developing specific types of malignancies is both clinically and biologically relevant. This relates to germ-cell tumors specifically in DSD patients with hypovirilization or gonadal dysgenesis. The presence of a well-defined part of the Y chromosome (known as the GBY region) is a prerequisite for malignant transformation, for which the testis-specific protein on the Y chromosome (TSPY ) is a likely candidate gene. The precursor lesions of these cancers are carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU) in testicular tissue and gonadoblastoma in those without obvious testicular differentiation. Most recently, undifferentiated gonadal tissue (UGT) has been identified as the likely precursor for gonadoblastoma. The availability of markers for the different developmental stages of germ cells allows detailed investigation of the characteristics of normal and (pre)malignant germ cells. Although informative in a diagnostic setting for adult male patients, these markers -such as OCT3/4 -cannot easily distinguish (pre)malignant germ cells from germ cells showing delayed maturation. This latter phenomenon is frequently found in gonads of DSD patients, and may be related to the risk of malignant transformation. Thus, the mere application of these markers might result in over-diagnosis and unnecessary gonadectomy. It is proposed that morphological and histological evaluation of gonadal tissue, in combination with OCT3/4 and TSPY double immunohistochemistry and clinical parameters, is most informative in estimating the risk for germ-cell tumor development in the individual patient, and might in future be used to develop a decision tree for optimal management of patients with DSD.

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Identification of recurrent chromosomal aberrations in germ cell tumors of neonates and infants using genomewide array‐based comparative genomic hybridization

Cited by 38 publications

References 39 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

Sacrococcygeal teratomas: clinico-pathological characteristics and isochromosome 12p status

Tumor risk in disorders of sex development (DSD)

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