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Novel amplicons in pediatric medulloblastoma identified by high-resolution genomic analysis: Genetic aberrations in medulloblastoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics. (Díaz de Ståhl)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Medulloblastoma (MB) is an aggressive and invasive embryonal CNS tumor that mainly affects children. Despite treatment, ~30% of the patients die within 2 years from diagnosis. MB patients are currently categorized into high- or standard-risk based on the clinical criteria, with high-risk group including patients <3 years, with incomplete tumor resection or with concomitant metastatic disease at presentation. However, these clinical parameters do not always predict patient outcome and additional biomarkers are desirable. In this study we have profiled a series of 25 MB samples with a high-resolution 32K BAC-array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations. The most frequent observed alteration was the combination of 17p loss and 17q gain, indicative of an isochromosome 17q, which was identified in 40% of the patients. This aberration was detected in both high- and standard-risk groups and was not associated with worse outcome. We also defined minimal overlapping regions of aberrations, including 16 regions of gains and 18 regions of loss in different chromosomes. Noteworthy, are a few very narrow amplified loci identified on autosomes 1, 3 and 8, aberrations that were verified with an alternative platform (Illumina 610Q chips). Several genes as CYR61, LMO4, EOMES, and MLH1 encompassed within these loci were also found to present with transcript up-regulation. These genes represent novel candidate genes most probably involved in MB development.

 

Keyword [en]
Medulloblastoma
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-121954OAI: oai:DiVA.org:uu-121954DiVA: diva2:306950
Available from: 2010-03-31 Created: 2010-03-31 Last updated: 2010-03-31
In thesis
1. Application of Genomic and Expression Arrays for Identification of new Cancer Genes
Open this publication in new window or tab >>Application of Genomic and Expression Arrays for Identification of new Cancer Genes
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Copy number variation (CNV) comprises a recently discovered kind of variation involving deletion and duplication of DNA segments of variable size, ranging from a few hundred basepairs to several million. By altering gene dosage levels or disrupting proximal or distant regulatory elements CNVs create human diversity. They represent also an important factor in human evolution and play a role in many disorders including cancer. Array-based comparative genomic hybridization as well as expression arrays are powerful and suitable methods for determination of copy number variations or gene expression changes in the human genome. In paper I we established a 32K clone-based genomic array, covering 99% of the current assembly of the human genome with high resolution and applied it in the profiling of 71 healthy individuals from three ethnic groups. Novel and previously reported CNVs, involving ~3.5% of the genome, were identified. Interestingly, 87% of the detected CNV regions overlapped with known genes indicating that they probably have phenotypic consequences. In papers II through IV we applied this platform to different tumor types, namely two collections of brain tumors, glioblastoma (paper II) and medulloblastoma (paper III), and a set of bladder carcinoma (paper IV) to identify chromosomal alterations at the level of DNA copy number that could be related to tumor initiation/progression. Tumors of the central nervous system represent a heterogeneous group of both benign and malignant neoplasms that affect both children and adults. Glioblastoma and medulloblastoma are two malignant forms. Glioblastoma often affects adults while the embryonal tumor medulloblastoma is the most common malignant brain tumor among children. The detailed profiling of 78 glioblastomas, allowed us to identify a complex pattern of aberrations including frequent and high copy number amplicons (detected in 79% of samples) as well as a number of homozygously deleted loci. These regions encompassed not only previously reported oncogenes and tumor suppressor genes but also numerous novel genes. In paper III, a subset of 26 medulloblastomas was analyzed using the same genomic array. We observed that alterations involving chromosome 17, especially isochromosome 17q, were the most common genomic aberrations in this tumor type, but copy number alterations involving other chromosomes: 1, 7 and 8 were also frequent. Focal amplifications, on chromosome 1 and 3, not previously described, were also detected. These loci may encompass novel genes involved in medulloblastoma development. In paper IV we examined for the presence of DNA copy number alterations and their effect on gene expression in a subset of 21 well-characterized Ta bladder carcinomas, selected for the presence or absence of recurrences. We identified a number of novel genes as well as a significant association between amplifications and high-grade and recurrent tumors which might be clinically useful.

The results derived from these studies increase our understanding of the genetic alterations leading to the development of these tumor forms and point out candidate genes that may be used in future as targets for new diagnostic and therapeutic strategies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 550
Keyword
Array-CGH, Expression array, Copy number variation, Glioblastoma, Medulloblastoma, Bladder carcinoma, Oncogenes, Tumor suppressor genes
National Category
Medical Genetics Medical Genetics Cell and Molecular Biology Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-121957 (URN)978-91-554-7775-2 (ISBN)
Public defence
2010-05-18, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2010-04-21 Created: 2010-03-31 Last updated: 2010-04-21Bibliographically approved

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Nord, Helena

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