title: Chromosomal Instability and Phosphoinositide Pathway Gene Signatures in Glioblastoma Multiforme.
abstract: 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 PI4K2A which encodes phosphatidylinositol 4-kinase type IIalpha. PI4K2A loss of heterozygosity mirrored that of PTEN, another enzyme that regulates phosphoinositide levels and also PIK3AP1, MINPP1, INPP5A and INPP5F. These results indicated a reduction in copy number for a set of phosphoinositide signalling genes that co-localise to chromosome 10q. This analysis was extended to a panel of phosphoinositide pathway genes on other chromosomes and revealed a number of previously unreported associations with glioblastoma multiforme. Of particular note were highly penetrant copy number losses for a group of X-linked phosphoinositide phosphatase genes OCRL, MTM1 and MTMR8; copy number amplifications for the chromosome 19 genes PIP5K1C, AKT2 and PIK3R2, and also for the phospholipase C genes PLCB1, PLCB4 and PLCG1 on chromosome 20. These mutations are likely to affect signalling and trafficking functions dependent on the PI(4,5)P2, PI(3,4,5)P3 and PI(3,5)P2 lipids as well as the inositol phosphates IP3, IP5 and IP6. Analysis of flanking genes with functionally unrelated products indicated that chromosomal instability as opposed to a phosphoinositide-specific 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 and this may be important for understanding drug resistance and phosphoinositide pathway redundancy in the advanced disease state.
authors.affiliation: Lipid and Membrane Biology Group, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK. m.waugh@ucl.ac.uk.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Waugh
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics*; D030541:Databases, Genetic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D010716:Phosphatidylinositols / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D010716:Phosphatidylinositols
keywords: Cancer; Gene copy number; Glioblastoma; PI 4-kinase