Abstract
High-resolution genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of glial brain tumors. We have done such mapping using cDNA microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade. This gene-by-gene approach permitted the precise sizing of critical amplicons and deletions and the detection of multiple new genetic aberrations. It has also revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships and showed that gliomas can be clustered into distinct genetic subgroups. A subset of detected alterations was shown predominantly associated with either astrocytic or oligodendrocytic tumor phenotype. Finally, five novel minimally deleted regions were identified in a subset of tumors, containing putative candidate tumor suppressor genes (TOPORS, FANCG, RAD51, TP53BP1, and BIK) that could have a role in gliomagenesis.
Highlights
Adult gliomas encompass a highly lethal group of tumors that includes astrocytomas, oligodendrogliomas, and oligoastrocytomas
The phenotypic and genotypic heterogeneity indicates that no isolated genetic event accounts for gliomagenesis but rather the cumulative effects of a number of alterations that operate in a concerted manner
We have precisely characterized genomic segments known from previous cytogenetic studies to be involved in gliomagenesis
Summary
Adult gliomas encompass a highly lethal group of tumors that includes astrocytomas, oligodendrogliomas, and oligoastrocytomas. Recurrent genomic regions of alteration in copy number, including net gains and losses, have been found in these neoplasms. Whereas some of these regions contain known (or candidate) oncogenes and tumor suppressor genes, the biologically relevant genes within other regions remain to be identified [1]. Comparative genomic hybridization (CGH) has been used to analyze DNA copy number changes in various human cancers, including gliomas [2, 3]. This karyotype-based method, has limited mapping resolution, and gains or losses must be several megabases in size to be detected. We have used 42,000-element array-CGH technology with the aim to generate highly precise and comprehensive gene copy number
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