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    Telomere sequence content can be used to determine ALT activity in tumours

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    Author
    Lee, M; Teber, ET; Holmes, O; Nones, K; Patch, A-M; Dagg, RA; Lau, LMS; Lee, JH; Napier, CE; Arthur, JW; ...
    Date
    2018-06-01
    Source Title
    Nucleic Acids Research
    Publisher
    OXFORD UNIV PRESS
    University of Melbourne Author/s
    Grimmond, Sean
    Affiliation
    Centre for Cancer Research
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Lee, M., Teber, E. T., Holmes, O., Nones, K., Patch, A. -M., Dagg, R. A., Lau, L. M. S., Lee, J. H., Napier, C. E., Arthur, J. W., Grimmond, S. M., Hayward, N. K., Johansson, P. A., Mann, G. J., Scolyer, R. A., Wilmott, J. S., Reddel, R. R., Pearson, J. V., Waddell, N. & Pickett, H. A. (2018). Telomere sequence content can be used to determine ALT activity in tumours. NUCLEIC ACIDS RESEARCH, 46 (10), pp.4903-4918. https://doi.org/10.1093/nar/gky297.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255025
    DOI
    10.1093/nar/gky297
    Abstract
    The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We then employed a machine learning approach to stratify tumours according to telomere repeat content with an accuracy of 91.6%. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. Overall, our approach demonstrates that telomere sequence content can be used to stratify ALT activity in cancers, and begin to define the molecular pathways involved in ALT activation.

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