Positional gene expression analysis identifies 12q overexpression and amplification in a subset of neuroblastomas

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Cancer Genetics and Cytogenetics (Impact Factor: 1.93). 11/2004; 154(2):131-7. DOI: 10.1016/j.cancergencyto.2004.02.009
Source: PubMed

ABSTRACT Neuroblastoma is a heterogeneous disease with variable clinical behaviors. Unique molecular features are associated with clinically relevant subgroups. We performed a comprehensive microarray gene expression analysis of 95 neuroblastomas in an effort to define clinically important molecular subtypes. A subset of tumors overexpressed several contiguous genes located at 12q13 approximately q15 and were studied further. By microarray, 5 of 95 neuroblastomas had overexpression of genes mapped to 12q13.1 approximately q15, suggesting an amplification event in this region. Positional expression mapping identified the narrowest region of overlap containing 21 genes, with 11 genes overexpressed in all five cases. Fluorescence in situ hybridization demonstrated 3 neuroblastomas with more than a 10-fold increase in 12q gene copies and 9 with 3- to 5-fold increases. Amplification and overexpression of genes at 12q13 approximately q15 were observed in a small subset of neuroblastomas. Although amplification of 12q has been previously reported in neuroblastoma cell lines, this is the first demonstration in tumor samples, and it defines a distinct subset that has not been described previously. The expressed genes mapped closely to the complex amplicon reported in sarcomas, and they identify critical genes and pathways affected by 12q gene amplification.

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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. "
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    ABSTRACT: Background Somatically 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. Methods Genomic 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. Results In 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). Conclusion NBs 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.
    PLoS ONE 07/2014; 9(7):e101990. DOI:10.1371/journal.pone.0101990 · 3.23 Impact Factor
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    • "Amplification of chromosome 12q13-q15, where CENTG1 is located, is frequently observed in numerous human cancers26,27,28,29. In 1994, Reifenberger et al revealed that CENTG1 is frequently co-amplified with cyclin-dependent kinase 4 (CDK4), which is a well-known proliferation activator that promotes E2F- and CDK2-dependent cell cycle progression in tumors28, it would be logical to surmise that PIKE-A amplification or overexpression coordinately acts with CDK4 amplification or overexpression to drive tumorigenesis. "
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    ABSTRACT: Tumorigenesis is the process by which normal cells evolve the capacity to evade and overcome the constraints usually placed upon their growth and survival. To ensure the integrity of organs and tissues, the balance of cell proliferation and cell death is tightly maintained. The proteins controlling this balance are either considered oncogenes, which promote tumorigenesis, or tumor suppressors, which prevent tumorigenesis. Phosphoinositide 3-kinase enhancer (PIKE) is a family of GTP-binding proteins that possess anti-apoptotic functions and play an important role in the central nervous system. Notably, accumulating evidence suggests that PIKE is a proto-oncogene involved in tumor progression. The PIKE gene (CENTG1) is amplified in a variety of human cancers, leading to the resistance against apoptosis and the enhancement of invasion. In this review, we will summarize the functions of PIKE proteins in tumorigenesis and discuss their potential implications in cancer therapy.
    Acta Pharmacologica Sinica 06/2013; 34(8). DOI:10.1038/aps.2013.71 · 2.91 Impact Factor
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    • "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]. "
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    ABSTRACT: Background Aggressive 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. Methods Based 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. Results MNA 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. Conclusion MNA 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.
    BMC Cancer 05/2013; 13(1):231. DOI:10.1186/1471-2407-13-231 · 3.36 Impact Factor
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