ABSTRACT
Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet loss of ATRX alone is insufficient to trigger ALT, suggesting that additional cooperating factors are involved. We identify H3.3G34R and IDH1/2 mutations as two such factors in ATRX-mutated glioblastomas. Both mutations are capable of inactivating histone demethylases, and we identify KDM4B as the key demethylase inactivated in ALT. Mouse embryonic stem cells inactivated for ATRX, TP53, TERT and KDM4B (KDM4B knockout or H3.3G34R) show characteristic features of ALT. Conversely, KDM4B over-expression in ALT cancer cells abrogates ALT-associated features. In this work, we demonstrate that inactivation of KDM4B, through H3.3G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in glioblastomas.
Subject(s)
Embryonic Stem Cells/metabolism , Glioblastoma/genetics , Histones/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Telomere Homeostasis/genetics , X-linked Nuclear Protein/genetics , Adult , Animals , Chromatin/genetics , Chromatin/metabolism , Chromatin Immunoprecipitation , Chromatin Immunoprecipitation Sequencing , DNA Replication/genetics , Gene Knockout Techniques , Glioblastoma/metabolism , Histone Demethylases/genetics , Histone Demethylases/metabolism , Histones/metabolism , Humans , In Situ Hybridization, Fluorescence , Isocitrate Dehydrogenase/genetics , Jumonji Domain-Containing Histone Demethylases/genetics , Mice , Mutation , Signal Transduction/genetics , Telomerase/genetics , Telomerase/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Up-RegulationABSTRACT
OBJECTIVES: To determine respondents reported levels of exposure to audit during their medical career and as a general practice non-principal. To assess and identify audit education and training needs. DESIGN: Postal questionnaire survey. SETTING: The West of Scotland. SUBJECTS: Two hundred GP non-principals. RESULTS: A response rate of 79% was achieved. The mean age of respondents was 35 years and 121 (77%) were female. One hundred and thirty respondents (83%) reported involvement in three or less audit projects during a mean career length of 12.1 years. Of 378 audit projects claimed to have been undertaken, 287 (76%) involved setting measurable standards, and 181 (48%) failed to be completed. One hundred and six respondents (68%) had yet to take part in audit during their time as a non-principal (median length of time was 1 year). Thirty nine respondents (25%) were currently involved in an on-going audit project. One hundred and twelve (71%) claimed that they were not expected to participate in audit as part of their current or previous non-principal post. One hundred and one respondents (64%) indicated that they require further education and training in audit method. CONCLUSIONS: Non-principals' experience of audit and exposure to it are poor. Many lack knowledge of audit method and appear to be uninvolved in audit and excluded from local audit programmes. Integration into the primary care team, access to a co-ordinated programme of audit and training in audit method are required. Otherwise non-principals may continue to struggle with the audit demands of clinical governance and impending revalidation.
