cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma

Chen, Qing Rong; Bilke, Sven; Wei, Jun S.; Whiteford, Craig C.; Cenacchi, Nicola; Krasnoselsky, Alexei L.; Greer, Braden T.; Son, Chang Gue; Westermann, Frank; Berthold, Frank; Schwab, Manfred; Catchpoole, Daniel; Khan, Javed

doi:10.1186/1471-2164-5-70

Cited by 83 publications

(35 citation statements)

References 32 publications

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“…On average, non-MYCNA primary tumors had more CNAs and a greater proportion of the genome comprised of CNAs than MYCNA primaries (Fig. 1C), which is consistent with prior studies (Chen et al, 2004;Mosse et al, 2007). Moreover, regardless of MYCN status, CNS metastases had more CNAs and a (Matthay et al, 2003) 16 10 (63) 6 (37) All Pre-CNS primaries 27 14 (52) 13 (48) greater proportion of the genome comprised of CNAs, when compared with pre-CNS primaries (Fig.…”

Section: Cnas In Neuroblastoma Cns Metastases and Pre-cns Primariessupporting

confidence: 91%

Recurrent pre‐existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases

Cobrinik

Ostrovnaya

Hassimi

et al. 2013

Genes Chromosomes & Cancer

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Stage 4 neuroblastomas have a high rate of local and metastatic relapse and associated disease mortality. The central nervous system (CNS) is currently one of the most common isolated relapse sites, yet the genomic alterations that contribute to these metastases are unknown. This study sought to identify recurrent DNA copy number alterations (CNAs) and target genes relating to neuroblastoma CNS metastases by studying 19 pre-CNS primary tumors and 27 CNS metastases, including 12 matched pairs. SNP microarray analyses revealed that MYCN amplified (MYCNA) tumors had recurrent CNAs different from non-MYCNA cohorts. Several CNAs known to be prevalent among primary neuroblastomas occurred more frequently in CNS metastases, including 4p-, 7q+, 12q+, and 19q- in non-MYCNA metastases, and 9p- and 14q- irrespective of MYCNA status. In addition, novel CNS metastases-related CNAs included 18q22.1 gains in non-MYCNA pre-CNS primaries and 5p15.33 gains and 15q26.1→tel losses in non-MYCNA CNS metastases. Based on minimal common regions, gene expression, and biological properties, TERT (5p), NR2F2 (15q), ALDH1A3 (15q), CDKN2A (9p), and possibly CDH7 and CDH19 (18q) were candidate genes associated with the CNS metastatic process. Notably, the 5p15 minimal common region contained only TERT, and non-MYCNA CNS metastases with focal 5p15 gains had increased TERT expression, similar to MYCNA tumors. These findings suggest that a specific genomic lesion (18q22.1 gain) predisposes to CNS metastases and that distinct lesions are recurrently acquired during metastatic progression. Among the acquired lesions, increased TERT copy number and expression appears likely to function in lieu of MYCNA to promote CNS metastasis.

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Section: Cnas In Neuroblastoma Cns Metastases and Pre-cns Primariessupporting

confidence: 91%

Recurrent pre‐existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases

Cobrinik

Ostrovnaya

Hassimi

et al. 2013

Genes Chromosomes & Cancer

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“…There are other examples in the literature of neuroblastoma cell lines and tumors with very similar amplified regions at 11q13 [11,25] or 12q13–q15 [11,21,30], respectively, and in two tumors synchronous amplification on both chromosomes have been reported [11,31,32], as in the present case. CCND1 , IGHMBP2 , ORAOV1 , FGF4 on chromosome 11q13, and CDK4 and MDM2 on 12q13-15 are interesting oncogenes in this context.…”

Section: Discussionsupporting

confidence: 79%

“…However, those 11q13 amplified neuroblastomas which also displayed MNA were diagnosed at earlier ages [11]. Clinical information on 12q amplified neuroblastoma is sparse in the literature but indicates advanced disease [30,33,34]. MNA may occur also in 12q amplified neuroblastoma [21,30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Clinical information on 12q amplified neuroblastoma is sparse in the literature but indicates advanced disease [30,33,34]. MNA may occur also in 12q amplified neuroblastoma [21,30,31]. Amplicons of other chromosomal regions are described in single cases of poor outcome neuroblastoma, involving 16q.21, 4q.33, 6p12-21 [25], 5q33.3 [11], and the MYC containing 8q24 region [26].…”

Section: Discussionmentioning

confidence: 99%

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Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation

et al. 2013

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BackgroundAggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. The purpose of the present work was to characterize the genetic and clinical diversity of such tumors by high resolution arrayCGH profiling.MethodsBased on a 32K BAC whole-genome tiling path array and using 50-250K Affymetrix SNP array platforms for verification, DNA copy number profiles were generated for 34 consecutive high-risk or lethal outcome neuroblastomas. In addition, age and MYCN amplification (MNA) status were retrieved for 112 unfavorable neuroblastomas of the Swedish Childhood Cancer Registry, representing a 25-year neuroblastoma cohort of Sweden, here used for validation of the findings. Statistical tests used were: Fisher’s exact test, Bayes moderated t-test, independent samples t-test, and correlation analysis.ResultsMNA or segmental 11q loss (11q-) was found in 28/34 tumors. With two exceptions, these aberrations were mutually exclusive. Children with MNA tumors were diagnosed at significantly younger ages than those with 11q- tumors (mean: 27.4 vs. 69.5 months; p=0.008; n=14/12), and MNA tumors had significantly fewer segmental chromosomal aberrations (mean: 5.5 vs. 12.0; p<0.001). Furthermore, in the 11q- tumor group a positive correlation was seen between the number of segmental aberrations and the age at diagnosis (Pearson Correlation 0.606; p=0.037). Among nonMNA/non11q- tumors (n=6), one tumor displayed amplicons on 11q and 12q and three others bore evidence of progression from low-risk tumors due to retrospective evidence of disease six years before diagnosis, or due to tumor profiles with high proportions of numerical chromosomal aberrations. An early age at diagnosis of MNA neuroblastomas was verified by registry data, with an average of 29.2 months for 43 cases that were not included in the present study.ConclusionMNA and segmental 11q loss define two major genetic variants of unfavorable neuroblastoma with apparent differences in their pace of tumor evolution and in genomic integrity. Other possible, but less common, routes in the development of aggressive tumors are progression of low-risk infant-type lesions, and gene amplifications other than MYCN. Knowledge on such nosological diversity of aggressive neuroblastoma might influence future strategies for therapy.

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“…The most frequent amplifications concern ALK amplification at band 2p23, frequently co-amplified with MYCN , accounting for 4% of NBs studied in a meta-analysis [33]–[35], found in five cases in our study (group 2) and ODC1 amplification at band 2p25 always found co-amplified with MYCN (20% of cases analysed in 2 studies) [9], [30], found in three cases in our study (group 2). Somatic amplification at 12q13–15 locus has also been described [6], [9], [12], [14]–[16], [19], [36]. This amplified region contains two potential target genes: CDK4 (12q13_14) involved in cell cycle progression and MDM2 (12q15), a target gene of the transcription factor tumour protein p53 and the encoded protein can target p53 for proteasomal degradation.…”

Section: Discussionmentioning

confidence: 98%

Clinical Characteristics and Outcome of Patients with Neuroblastoma Presenting Genomic Amplification of Loci Other than MYCN

et al. 2014

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BackgroundSomatically acquired genomic alterations with MYCN amplification (MNA) are key features of neuroblastoma (NB), the most common extra-cranial malignant tumour of childhood. Little is known about the frequency, clinical characteristics and outcome of NBs harbouring genomic amplification(s) distinct from MYCN.MethodsGenomic profiles of 1100 NBs from French centres studied by array-CGH were re-examined specifically to identify regional amplifications. Patients were included if amplifications distinct from the MYCN locus were seen. A subset of NBs treated at Institut Curie and harbouring MNA as determined by array-CGH without other amplification was also studied. Clinical and histology data were retrospectively collected.ResultsIn total, 56 patients were included and categorised into 3 groups. Group 1 (n = 8) presented regional amplification(s) without MNA. Locus 12q13-14 was a recurrent amplified region (4/8 cases). This group was heterogeneous in terms of INSS stages, primary localisations and histology, with atypical clinical features. Group 2 (n = 26) had MNA as well as other regional amplifications. These patients shared clinical features of those of a group of NBs MYCN amplified (Group 3, n = 22). Overall survival for group 1 was better than that of groups 2 and 3 (5 year OS: 87.5%±11% vs 34.9%±7%, log-rank p<0.05).ConclusionNBs harbouring regional amplification(s) without MNA are rare and seem to show atypical features in clinical presentation and genomic profile. Further high resolution genetic explorations are justified in this heterogeneous group, especially when considering these alterations as predictive markers for targeted therapy.

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cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma

Abstract: Background: Recurrent non-random genomic alterations are the hallmarks of cancer and the characterization of these imbalances is critical to our understanding of tumorigenesis and cancer progression.

Cited by 83 publications

References 32 publications

Recurrent pre‐existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases

Recurrent pre‐existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases

Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation

Clinical Characteristics and Outcome of Patients with Neuroblastoma Presenting Genomic Amplification of Loci Other than MYCN

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