Comparative Genomic Hybridization (Cgh) Analysis of Neuroblastomas—an Important Methodological Approach in Paediatric Tumour Pathology

Brinkschmidt, Christian; Christiansen, Holger; Terpe, Hans-Joachim; Simon, Ronald; Boecker, Werner; Lampert, F.; Stoerkel, Stefan

doi:10.1002/(sici)1096-9896(199704)181:4<394::aid-path800>3.0.co;2-1

Cited by 93 publications

(51 citation statements)

References 21 publications

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“…25 Our PCC results were similar to neuroblastoma with a prevalence of losses on 1p and gains on the distal end of 17q. The gains of 17q never reported before in PCC emerged as the most important genetic result in our study.…”

Section: Discussionsupporting

confidence: 73%

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

August¹,

August²,

Schroeder³

et al. 2004

Modern Pathology

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The natural course of pheochromocytomas (PCC) cannot be predicted for certain on the basis of primary histology, their malignant character can only be confirmed by the occurrence of metastases during follow-up. Based on the recently proposed PASS score for evaluation we examined 37 adrenal (36 sporadic and one familial) and six sporadic extra-adrenal paragangliomas (all designated as pheochromocytomas) with a 'malignant histology' to find additional predictive factors. Drawing upon the follow-up (18 months to 12 years, mean 5.8 years) metastasized (n ¼ 20) and nonmetastasized (n ¼ 23) courses could be distinguished. Metastasized PCC revealed significantly (P ¼ 0.03) more copy number changes on comparative genomic hybridization (CGH) (mean 8.3) than nonmetastasized tumors (mean: 4.3). The most frequent chromosomal alterations were losses on 1p (75.6%) and 3q (44%). Both were detected with identical frequency in metastasized and nonmetastasized PCC. A gain on 17q (P ¼ 0.025) was significantly predominant in malignant courses and suggests similarities in the genetic origin and progression of PCC and neuroblastomas. The proliferative activity (MIB-1 score) of metastasized PCC (n ¼ 20) was found to be significantly higher in metastasized tumors (mean 12.8% vs mean 3.5%). In contrast, the semiquantitatively scored membrane-bound staining of CD 44-S was stronger in tumors without metastases (mean 2.1 vs mean: 0.25) during the follow-up period (Po0.01). Although the results correspond to the established weight differences the tumor weight does not appear to be an independent prognostic factor. Our study suggests that CD 44-S and MIB-1 immunostaining as well as the CGH results might complement the PASS score in predicting a metastasized course of PCC. Regardless of tumor weight, tumors with a 'malignant histology' are highly prone to metastasize when more than 5% of MIB1-positive nuclei are present or CD44-S immunostaining is negative, or both. PCC with 10 or more copy number changes on CGH must be referred to as malignant tumors. The safe distinction between benign and malignant pheochromocytomas (PCC) is an unresolved dilemma beleaguering diagnostic pathology to the present day. In most cases the decision is therefore based on the occurrence of metastases as the only proof of malignancy. Recently, Thompson 1 proposed an adrenal gland scoring scale (PASS) capable of determining malignancy solely on the grounds of conventional histological criteria. Within the framework of this scoring scale, less prognostic importance is attributed to vascular and capsular invasion (with a score of 1 point each) than to growth pattern, necroses and characteristics of proliferative behavior (high cellularity, cellular monotony, more than three mitoses/10 HPF and the occurrence of atypical mitoses). These characteristics each have a score of two points).In recent reports on adrenal and extra-adrenal PCC a number of chromosomal aberrations were discussed with a view to their possible involvement

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Section: Discussionsupporting

confidence: 73%

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

August¹,

August²,

Schroeder³

et al. 2004

Modern Pathology

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“…Chromosome CGH, and more recently array-CGH, are techniques of choice for assessing such imbalances in a single experiment (Kallioniemi et al, 1992). To date, several series of CGH analyses of non-selected NBs including MYCN amplified cases have been published, mostly consisting of data from several centres (Brinkschmidt et al, 1997;Vandesompele et al, 2005). These previous analyses have shown that, using CGH, tumours could be classified into genomic groups associated with distinct clinical characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…Chromosome CGH analysis of NB samples has enabled the identification of distinct genetic subtypes with specific prognostic characteristics (Brinkschmidt et al, 1997(Brinkschmidt et al, , 1998Vandesompele et al, 1998Vandesompele et al, , 2001Plantaz et al, 2001). A genomic profile characterised by whole chromosome gains or losses, defining type 1 tumours , is observed more frequently in localised tumours and in children less than 1 year of age, with a good prognosis.…”

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confidence: 99%

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

et al. 2007

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Whereas neuroblastoma (NB) with MYCN amplification presents a poor prognosis, no single marker allows to reliably predict outcome in tumours without MYCN amplification. We report here an extensive analysis of 147 NB samples at diagnosis, without MYCN amplification, by chromosomal comparative genomic hybridisation (CGH), providing a comprehensive overview of their genomic imbalances. Comparative genomic hybridisation profiles showed gains or losses of entire chromosomes (type 1) in 71 cases, whereas partial chromosome gains or losses (type 2), including gain involving 17q were observed in 68 cases. Atypical profiles were present in eight cases. A type 1 profile was observed more frequently in localised disease (Po0.0001), and in patients of less than 12 months at diagnosis (Po0.0001). A type 2 genomic profile was associated with a higher risk of relapse in the overall population (logrank test; Po0.0001), but also in the subgroup of patients with localised disease (log-rank test, P ¼ 0.007). In multivariate analysis, the genomic profile was the strongest independent prognostic factor. In conclusion, the genomic profile is of prognostic impact in patients without MYCN amplification, making it a help in the management of low-stage NB. Further studies using higher-resolution CGH are needed to better characterise atypical genomic alterations.

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“…gain of 11q, as a marker for all tumorigenic cell populations. Gain of 11q is seen in a number of tumors (Bockmuhl et al, 1996;Brinkschmidt et al, 1997;Mahlamaki et al, 1997;Tirkkonen et al, 1998) but was so far not described for skin carcinomas. Own preliminary data indicate a similar gain of 11q (including the area of q13) in skin SCC cell lines and primary tumors (SCCs and benign keratoacanthomas) (Popp and Boukamp, in preparation).…”

Section: Discussionmentioning

confidence: 99%

Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature

et al. 1999

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UV-radiation is a major risk factor for non-melanoma skin cancer causing speci®c mutations in the p53 tumor suppressor gene and other genetic aberrations. We here propose that elevated temperature, as found in sunburn areas, may contribute to skin carcinogenesis as well. Continuous exposure of immortal human HaCaT skin keratinocytes (possessing UV-type p53 mutations) to 408C reproducibly resulted in tumorigenic conversion and tumorigenicity was stably maintained after recultivation of the tumors. Growth at 408C was correlated with the appearance of PARP, an enzyme activated by DNA strand breaks and the level corresponded to that seen after 5 Gy g-radiation. Concomitantly, comparative genomic hybridization (CGH) analyis demonstrated that chromosomal gains and losses were present in cells maintained at 408C while largely absent at 378C. Besides individual chromosomal aberrations, all tumor-derived cells showed gain of chromosomal material on 11q with the smallest common region being 11q13.2 to q14.1. Cyclin D1, a candidate gene of that region was overexpressed in all tumor-derived cells but cyclinD1/ cdk4/cdk6 kinase activity was not increased. Thus, these data demonstrate that long-term thermal stress is a potential carcinogenic factor in this relevant skin cancer model, mediating its e ect through induction of genetic instability which results in selection of tumorigenic cells characterized by gain of 11q.

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Comparative Genomic Hybridization (Cgh) Analysis of Neuroblastomas—an Important Methodological Approach in Paediatric Tumour Pathology

Cited by 93 publications

References 21 publications

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature

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