High-Resolution Genome-Wide Mapping of Genetic Alterations in Human Glial Brain Tumors

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. (Cancer Res 2005; 65(10): 4088-96)

Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

“…Clinical examinations have revealed that Mnk1 is significantly elevated in human glioma tissues (18). Several studies have shown that the potent Mnk inhibitor CGP57380 suppresses human cancer cell growth in vitro (31,(37)(38)(39), but it remains unclear whether this inhibition is due to effects on Mnk1/2 or on Mnk1/2 plus other kinases promoting cell growth (40,41).…”

“…Enhanced eIF4E phosphorylation has been observed in various solid tumors (13) and lymphomas (14) and correlates with poor patient prognosis, particularly in non-smallcell lung cancer (15). Furthermore, Mnk1 is highly expressed in hematological malignancies (16,17), and both Mnk1 and Mnk2 are up-regulated in solid tumors such as gliomas and ovarian cancers (18,19). Consistent with these clinical findings, in vitro studies have shown that NIH 3T3 cells expressing phosphodefective eIF4E display diminished transformation activity, whereas overexpression of wild-type (WT) eIF4E fully transforms this cell line (20,21).…”

Molecular Epidemiology of Primary Brain Tumors

“…Their result indicated that 15q23-q26.3 harbors a novel susceptibility allele for familial glioma, and since their finding, improved higher resolution molecular genetic technology has marked the progress of mapping genetic changes in PBTs. Bredel et al 27 conducted a high-resolution mapping by using cDNA microarray CGH technology to profile genetic changes with 42,000 cDNA clones in a cohort of 54 glioma patients and identified five novel minimally deleted loci thought to be important in gliomagenesis. The study successfully predicted astrocytoma and oligodendroglioma with 92% and 88% accuracy, respectively, based on 170 gene copy number patterns.…”

ACTuDB, a new database for the integrated analysis of array-CGH and clinical data for tumors

“…The website is powered by an Apache server. Blaveri et al (2005) 92.9 Bredel et al (2005) 91.7 Gysin et al (2005) 92.6 Janoueix- Lerosey et al (2005) 97.4 Mosse et al (2005) 61.7 Patil et al (2005) 92.8 Snijders et al (2005) 93.2 de Leeuw et al (2004) 71.5 Douglas et al (2004) 99.3 Nakao et al (2004) 93.0 Woodfine et al (2004) 99.8 Veltman et al (2003) 74.2 Chen et al (2002) 83.8 Pollack et al (2002) 88.5 Snijders et al (2001) 89 …”

“…Many studies have been carried out on bladder cancer (Veltman et al, 2003;Blaveri et al, 2005;Stransky et al, 2006), brain cancer (Bredel et al, 2005;Kotliarov et al, 2006), breast cancer (Pollack et al, 2002;Fridlyand et al, 2006), colon cancer (Douglas et al, 2004;Nakao et al, 2004), liver cancer (Patil et al, 2005), lymphoma (de Leeuw et al, 2004), neuroblastoma (JanoueixLerosey et al, 2005;Mosse et al, 2005), mouth cancer (Snijders et al, 2005), pancreas cancer (Gysin et al, 2005) and replication timing (Woodfine et al, 2004;Janoueix-Lerosey et al, 2005). Comparisons of the results of experiments from different laboratories, on different types of cancer, are required to validate results or hypotheses and to improve our understanding of the recurrent alterations involved in cancer.…”