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  • br Please cite this article as Bacolla A et

    2020-08-28


    Please cite this article as: Bacolla, A et al., Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.03.004
    8 A. Bacolla et al. / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
    Fig. 4. Altered gene expression in key pathways decreases patient survival. Panel A, box plot of the correlation coefficient R for the coexpression of MYBL2 vs. CENPA, KIF2C or KIFC1 in patients for each of the 32 TCGA tumor types. Panels B and C, line plots for the normalized Rsem gene expression values for MYBL2 vs. KIFC1 in LGG patients (panel B) and vs. KIF2C in BRCA patients (panel C). R, regression coefficient; P, P-value. Panel D, list of tumor types with worse survival for high MYBL2 gene expression levels and P-values for the respective Kaplan-Meier survival curves. Panel E, Kaplan-Meier survival curves for MESO patients with low (red) and high (blue) gene expression levels for MYBL2. Panel F, list of tumor types in which expression of the succinate dehydrogenase complex genes was lower in the tumor than in the matched control tissues and the corresponding P-values. Panel G, Kaplan-Meier survival curves for KIRC patients with low (red) and high (blue) SDHD gene expression.
    1000 patients (Fig. 4C). We applied the KM estimator analysis for MYBL2 to all tumor types. Poor prognosis was associated with high MYBL2 expression in 11/32 tumors (Fig. 4D), with particularly dismal outcome in patients with ACC, KIRC and MESO (Fig. 4E). Thus, our analysis supports a role for MYBL2 overexpression in carcinogenesis in approximately one third of tumor types.
    SDHAF3 (succinate dehydrogenase complex assembly factor 3) is
    defined as playing “an essential role in the assembly of succinate dehydrogenase (SDH). SDH is an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricar-boxylic OSMI-4 (TCA) cycle and the mitochondrial electron transport chain. SDH couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. SDHAF3 pro-motes maturation of the iron-sulfur protein subunit SDHB of the
    Please cite this article as: Bacolla, A et al., Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.03.004
    A. Bacolla et al. / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx 9
    Please cite this article as: Bacolla, A et al., Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.03.004
    10 A. Bacolla et al. / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
    SDH catalytic dimer, protecting it from the deleterious effects of oxidants” (https://www.genecards.org/). The SDH complex com-prises four subunits (SDHA-D), which perform catalysis and elec-tron transfer, and 4 accessory proteins, SDHAF1-4. In PRAD, where SDHAF3 displayed the strongest negative correlation between expression and mutation of all tumors, the gene was overexpressed relative to matched controls (not shown); however, SDHD was strongly downregulated. An analysis of gene expression for the 8 SDH genes in the 15 tumor/normal pairs revealed that, with the exception of LUSC, at least one SDH gene subunit (most often SDHD) was downregulated in all tumors, often dramatically (P < 1 10 10) (Fig. 4F). In addition, in KIRC, where 5/8 SDH genes were strongly repressed, the KM estimator predicted worse clinical outcome in subjects with low SDHD. Thus, our gene expression/mutations re-lationships provide support for SDH deficiency as a widespread alteration in cancer.
    3.2.4. Mutation loads are associated with defects in DNA repair Having established the validity of our analyses in uncovering
    genes whose deregulation seem to predict poor clinical outcome, we then conducted a systematic assessment of gene enrichment for a pool of genes with strong correlations in each tumor type. We chose as a threshold for the number of genes those whose expression was positively correlated with mutations, in LUAD, with a P-value <1 10 10, which totaled 270. We then selected the same number of genes for the other tumor types. We conducted a gene enrichment analysis focused on KEGG terms, which are suited for identifying cellular pathways. Three tumor types, KICH, LUAD and PRAD shared commonly enriched gene categories, including “Cell cycle”, “DNA replication” and major DNA repair pathways, including the “Fanconi anemia pathway”, “Mismatch repair” (MMR), “Homologous recombination” (HR), “Nucleotide excision repair” (NER) and “Base excision repair” (BER) (Fig. 5A). A fourth tumor type (LGG) shared these pathways with reduced strength. A second set of tumors (STAD, THCA and CHOL) also shared distinct terms, such as Parkinson’s, Alzheimer’s, Huntington’s diseases, and “Oxidative phosphorylation”, all of which contained genes coding for complexes I e V of the mitochondrial respiratory chain (Fig. 5B). For STAD these genes were: NDUFB10, NDUFA8, NDUFA9, NDUFA6, NDUFB9, NDUFAB1, NDUFS7, NDUFV1, NDUFS3, NDUFS2 for complex I, SDHB, SDHD for complex II, UQCRC2, UQCRC1, CYC1 for complex III, COX4I1, COX5A for complex IV and ATP5D, ATP5B, ATP5F1, ATP5G3, ATP5O, ATP5A1 for complex V.