Structural rearrangements of chromosome 10 are frequently observed in glioblastoma multiforme

Structural rearrangements of chromosome 10 are frequently observed in glioblastoma multiforme and over 80?% of tumour samples archived in the catalogue of somatic mutations in cancer database had gene copy number loss for which encodes phosphatidylinositol 4-kinase type IIalpha. process underlay this pattern of copy number variation. This in silico study suggests that in glioblastoma multiforme karyotypic changes have the potential to cause multiple abnormalities in sets of genes involved in phosphoinositide metabolism Sapitinib and this may be important for understanding drug resistance and phosphoinositide pathway redundancy in the advanced disease state. mutations are associated with this disease. Several studies have demonstrated that PI4K2A controls the signalling and trafficking of cell surface receptors such as EGFR [30-32] and HER2 [33] which are known to stimulate oncogenic signalling. EGFR is often overexpressed in glioblastoma [12] and anti-EGFR therapies are a potential targeted therapy in this difficult-to-treat disease [4 13 34 In addition to EGFR overexpression loss of the tumour suppressor PTEN is a common feature in glioblastoma Sapitinib [1 41 PTEN is a phosphoinositide 5-phosphatase that in normal cells rapidly dephosphorylatesthe PI3K lipid product PI(3 4 5 which is a potent stimulator of signalling via the Akt/mTOR pathway [44-47]. Deletion of results in sustained and elevated PI3K signalling and augmented cell proliferation [48]. Given that PI4KIIα has roles in regulating both EGFR and AKT signalling an initial aim of this study was to ascertain if the gene is mutated in glioblastoma. Through analysis of publically accessible genomic data available via the COSMIC resource we were able to establish that point mutations of were rare in glioblastoma but more than 80?% of samples from a cohort of 638 exhibited loss of heterozygosity; this level of copy number variation mirrored that of which also localises to chromosome 10p. Methods Genomic Analysis The Catalogue of Somatic Mutations In Cancer (COSMIC) bioinformatics resource (http://www.sanger.ac.uk/cosmic) [49 50 established and maintained by the Wellcome Trust Sanger Institute was used in order to identify mutations in the 638 individual tumour samples analysed by the Cancer Genome Atlas (TCGA). For these samples in the COSMIC database gene copy number analysis was carried out using ASCAT (Allele-Specific Copy number Analysis of Tumours) algorithm software [51] available at http://heim.ifi.uio.no/bioinf/Projects/ASCAT. For this analysis the average copy number for the genome is 1.90 and a reduction in total copy number to a value of 1 1.30 or less demarcates a loss while a?gain was?set at?copy number ≥ 3. Protein Rabbit Polyclonal to USP42. Expression Analysis The Human Protein Atlas [52 53 (www.proteinatlas.org) online resource was utilised to investigate the expression of candidate proteins identified from the genomic analyses in immunohistochemically stained control cerebral cortex tissue and glioblastoma patient samples. The immunohistochemical data included here derives only from antibodies that also detected the correct size protein band on Western blots. String Analysis The String [54] Search Tool for the Retrieval of Interacting Genes/Proteins software (http://string-db.org) was used to visualise interactions and networks amongst the protein products from the phosphoinositide pathway genes identified as having the highest levels of copy number variation in glioblastoma. Results and Discussion As a first step we sought to determine if there was any evidence for PI 4-kinase mutations in glioblastoma. We used the COSMIC resource and genomic data from 638 different glioblastoma patient samples to investigate the mutational status of the 4 human Sapitinib PI 4-kinase genes copy number and this was not seen for any of the other PI 4-kinase genes (Fig.?1). The pattern of copy number variation was also compared with a panel of established oncogenes and tumour suppressors composed of and (Fig.?1). From this initial comparison it became apparent that the level Sapitinib of gene copy number loss in glioblastoma mirrored that of a tumour suppressor such as as opposed to an oncogene such as that had an increased copy number. The loss of heterozgosity for and is biologically significant as these genes both localise to chromosome 10q and suggests that their copy number variation was due to a chromosome 10q deletion. For this to be the case then the nearest neighbour genes to should also undergo a similar degree of gene copy number loss. To investigate this possibility two genes immediately upstream Sapitinib and downstream of were identified. The upstream genes at the 10q24.2 locus were and while the immediate downstream.

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