A Way To Protect You Against Wortmannin Mishaps

Whereas CIC mutations were present in 13/16 (81%) of our oligodendroglioma exome libraries, the GSC database search revealed that CIC alterations in general are rare��0% of normal libraries and only 7.3% of libraries from other non-oligodendroglial cancers. Of the 21 mutations detected in the 20 CIC-mutant oligodendrogliomas (one carrying two distinct mutations), nine were clustered in exon 5 within an annotated DNA-interacting domain, three were in exon 20 within an annotated protein-interacting domain, and the remaining nine were in other exons (Figure 1). We also detected recurrent somatic mutations resulting in p.Arg201Trp and p.Arg215Trp changes and a recurrent out-of-frame deletion at chr19 : 47483653delTCC in exon 5. Another recurrent somatic mutation http://www.selleckchem.com/products/LY294002.html in codon 1515 of exon 20, leading to change of Arg > His and Arg > Leu, was also identified. When the rare CIC mutations were identified in the GSC human variant database, exons 5 and 20 mutations were represented in 8.6% of non-oligodendroglial tumours but disproportionally in 69% of oligodendrogliomas. Similarly, a survey of the Catalogue of Somatic Mutations in Cancer (COSMIC v54) database showed ten reported mutations in CIC, none occurring in exon 5 or 20. To assess the significance of the clustering of somatic mutations in CIC exons 5 and 20, we performed multiple sequence alignments using CLUSTALW 35. This analysis revealed that CIC exon 5 encoded http://www.selleck.cn/products/wortmannin.html a conserved annotated DNA-binding region, while exon 20 encoded a conserved domain lacking annotation in humans (Supporting information, Supplementary materials and methods). Side-by-side alignments of human and fruit fly CIC protein sequences revealed that the second conserved region mapped to a protein�Cprotein interaction region, annotated in the fly as the ��GRO-L interaction region�� http://www.selleckchem.com/products/CHIR-99021.html (not shown). Focused PCR and Sanger sequencing of CIC exons 5 and 20 was then performed on an extension set of 111 primary glioma specimens including 68 oligodendrogliomas (WHO II and III), 11 mixed oligoastrocytomas (WHO II and III), 32 astrocytomas (WHO II�CIV), and four normal brain specimens. The association of CIC mutations with 1p/19q co-deleted oligodendrogliomas was seen again in this cohort. In this extension set, 15 mutations were detected, of which 14 (93%) were found in IDH1-mutated, 1p/19q co-deleted oligodendrogliomas (see the Supporting information, Supplementary materials and methods for a detailed list of samples and mutations). Of the 204 tumour samples studied (16 discovery set exome and CIC deep sequenced, 77 CIC deep sequenced, and 111 CIC ex5/20 Sanger sequenced), 191 were informative for CIC, IDH1/2, and 1p/19q. CIC mutations were closely associated with classic oligodendroglioma histology (p