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High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors.

ABSTRACT: Medulloblastomas and supratentorial primitive neuroectodermal tumors are aggressive childhood tumors. We report our findings using array comparative genomic hybridization (CGH) on a whole-genome BAC/PAC/cosmid array with a median clone separation of 0.97 Mb to study 34 medulloblastomas and 7 supratentorial primitive neuroectodermal tumors. Array CGH allowed identification and mapping of numerous novel, small regions of copy number change to genomic sequence in addition to the large regions already known from previous studies. Novel amplifications were identified, some encompassing oncogenes MYCL1, PDGFRA, KIT, and MYB not previously reported to show amplification in these tumors. In addition, one supratentorial primitive neuroectodermal tumor had lost both copies of the tumor-suppressor genes CDKN2A and CDKN2B. Ten medulloblastomas had findings suggestive of isochromosome 17q. In contrast to previous reports using conventional CGH, array CGH identified 3 distinct breakpoints in these cases: Ch 17: 17940393-19251679 (17p11.2, n = 6), Ch 17: 20111990-23308272 (17p11.2-17q11.2, n = 4), and Ch 17: 38425359-39091575 (17q21.31, n = 1). Significant differences were found in the patterns of copy number change between medulloblastomas and supratentorial primitive neuroectodermal tumors, providing further evidence that these tumors are genetically distinct despite their morphologic and behavioral similarities.

SUBMITTER: McCabe MG

PROVIDER: S-EPMC2816352 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors.

McCabe Martin Gerard MG Ichimura Koichi K Liu Lu L Plant Karen K Bäcklund L Magnus LM Pearson Danita M DM Collins Vincent Peter VP

Journal of neuropathology and experimental neurology 20060601 6

Medulloblastomas and supratentorial primitive neuroectodermal tumors are aggressive childhood tumors. We report our findings using array comparative genomic hybridization (CGH) on a whole-genome BAC/PAC/cosmid array with a median clone separation of 0.97 Mb to study 34 medulloblastomas and 7 supratentorial primitive neuroectodermal tumors. Array CGH allowed identification and mapping of numerous novel, small regions of copy number change to genomic sequence in addition to the large regions alrea ...[more]

PMID: 16783165

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Project description:IntroductionGenomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution.MethodsWe employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines.ResultsCommon amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses.ConclusionHigh resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets.

Project description:BackgroundSmall intestinal neuroendocrine tumors (SI-NETs) are typically slow-growing tumors that have metastasized already at the time of diagnosis. The purpose of the present study was to further refine and define regions of recurrent copy number (CN) alterations (CNA) in SI-NETs.MethodsGenome-wide CNAs was determined by applying array CGH (a-CGH) on SI-NETs including 18 primary tumors and 12 metastases. Quantitative PCR analysis (qPCR) was used to confirm CNAs detected by a-CGH as well as to detect CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering was used to detect tumor groups with similar patterns of chromosomal alterations based on recurrent regions of CN loss or gain. The log rank test was used to calculate overall survival. Mann-Whitney U test or Fisher's exact test were used to evaluate associations between tumor groups and recurrent CNAs or clinical parameters.ResultsThe most frequent abnormality was loss of chromosome 18 observed in 70% of the cases. CN losses were also frequently found of chromosomes 11 (23%), 16 (20%), and 9 (20%), with regions of recurrent CN loss identified in 11q23.1-qter, 16q12.2-qter, 9pter-p13.2 and 9p13.1-11.2. Gains were most frequently detected in chromosomes 14 (43%), 20 (37%), 4 (27%), and 5 (23%) with recurrent regions of CN gain located to 14q11.2, 14q32.2-32.31, 20pter-p11.21, 20q11.1-11.21, 20q12-qter, 4 and 5. qPCR analysis confirmed most CNAs detected by a-CGH as well as revealed CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering of recurrent regions of CNAs revealed two separate tumor groups and 5 chromosomal clusters. Loss of chromosomes 18, 16 and 11 and gain of chromosome 20 were found in both tumor groups. Tumor group II was enriched for alterations in chromosome cluster-d, including gain of chromosomes 4, 5, 7, 14 and gain of 20 in chromosome cluster-b. Gain in 20pter-p11.21 was associated with short survival. Statistically significant differences were observed between primary tumors and metastases for loss of 16q and gain of 7.ConclusionOur results revealed recurrent CNAs in several candidate regions with a potential role in SI-NET development. Distinct genetic alterations and pathways are involved in tumorigenesis of SI-NETs.

Dataset Information

High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors.

Publications

High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors.

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