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  • br C G Loiselle L Edgar G Batist

    2020-08-28


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    Contents lists available at ScienceDirect
    Progress in Biophysics and Molecular Biology
    Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction
    Albino Bacolla, Zu Ye, Zamal Ahmed, John A. Tainer*
    Departments of Cancer Biology and of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX, 77030, USA
    Article history:
    Received in revised form
    Available online xxx
    Keywords:
    Genome instability
    G-quadruplexes
    Cancer mutations
    Translocation breakpoints
    Mitochondrial dysfunction
    Replication stress
    A hallmark of cancer is genomic instability, which can enable cancer Nigericin to evade therapeutic strategies. Here we employed a computational approach to uncover mechanisms underlying cancer mutational burden by focusing upon relationships between 1) translocation breakpoints and the thousands of G4 DNA-forming sequences within retrotransposons impacting transcription and exemplifying probable non-B DNA structures and 2) transcriptome profiling and cancer mutations. We determined the location and number of G4 DNA-forming sequences in the Genome Reference Consortium Human Build 38 and found a total of 358,605 covering ~13.4 million bases. By analyzing >97,000 unique translocation breakpoints from the Catalogue Of Somatic Mutations In Cancer (COSMIC), we found that breakpoints are overrepresented at G4 DNA-forming sequences within hominid-specific SVA retrotransposons, and generally occur in tumors with mutations in tumor suppressor genes, such as TP53. Furthermore, cor-relation analyses between mRNA levels and exome mutational loads from The Cancer Genome Atlas (TCGA) encompassing >450,000 gene-mutation regressions revealed strong positive and negative as-sociations, which depended upon tissue of origin. The strongest positive correlations originated from genes not listed as cancer genes in COSMIC; yet, these show strong predictive power for survival in most tumor types by Kaplan-Meier estimation. Thus, correlation analyses of DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate processes shaping genomic instability in cancer. The combined results point to G4 DNA, activation of cell cycle/DNA repair pathways, and mitochondrial dysfunction as three major factors driving the accumu-lation of somatic mutations in cancer cells.
    © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
    1. Introduction
    Genomic instability, increased proliferation and escape from apoptosis are hallmarks of cancer (Macheret and Halazonetis, 2015). A recent survey of >11000 tumor samples identified ~300 genes (cancer-driver genes) whose somatic mutations in terms of base substitutions are directly linked to malignancy (Bailey et al., 2018). Another ~1100 genes may support tumorigenesis through alterations in their expression profiles as a consequence of copy-number alterations, gene fusions, and other types of genomic rearrangements (Zhang et al., 2018a,b). A separate study suggests
    * Corresponding author.
    E-mail addresses: [email protected] (A. Bacolla), [email protected]