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    Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

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    Author
    Knijnenburg, TA; Wang, L; Zimmermann, MT; Chambwe, N; Gao, GF; Cherniack, AD; Fan, H; Shen, H; Way, GP; Greene, CS; ...
    Date
    2018-04-03
    Source Title
    Cell Reports
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    Boussioutas, Alex; Corcoran, Niall; Costello, Anthony; Hovens, Christopher
    Affiliation
    Surgery (RMH)
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Knijnenburg, T. A., Wang, L., Zimmermann, M. T., Chambwe, N., Gao, G. F., Cherniack, A. D., Fan, H., Shen, H., Way, G. P., Greene, C. S., Liu, Y., Akbani, R., Feng, B., Donehower, L. A., Miller, C., Shen, Y., Karimi, M., Chen, H., Kim, P. ,... Wang, C. (2018). Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. CELL REPORTS, 23 (1), pp.239-+. https://doi.org/10.1016/j.celrep.2018.03.076.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255040
    DOI
    10.1016/j.celrep.2018.03.076
    Abstract
    DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

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