title: How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models.
abstract: Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.
authors.affiliation: Department of Radiation Oncology (MaastRO) Lab, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: m.vangisbergen@maastrichtuniversity.nl.
authors.forename: M W
authors.initials: MW
authors.lastname: van Gisbergen
authors.affiliation: Department of Radiation Oncology (MaastRO) Lab, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD Maastricht, The Netherlands; Department of Clinical Genomics, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: an.voets@maastrichtuniversity.nl.
authors.forename: A M
authors.initials: AM
authors.lastname: Voets
authors.affiliation: Department of Radiation Oncology (MaastRO) Lab, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD Maastricht, The Netherlands; Informatics and Bio-computing Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, ON M5G 0A3, Canada. Electronic address: maud.starmans@maastrichtuniversity.nl.
authors.forename: M H W
authors.initials: MH
authors.lastname: Starmans
authors.affiliation: Department of Neurology, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Electronic address: i.decoo@erasmusmc.nl.
authors.forename: I F M
authors.initials: IF
authors.lastname: de Coo
authors.affiliation: Department of Neurology, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Electronic address: r.yadak@erasmusmc.nl.
authors.forename: R
authors.initials: R
authors.lastname: Yadak
authors.affiliation: European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Deusinglaan 1, NL-9713 AV Groningen, The Netherlands. Electronic address: r.f.hoffmann@umcg.nl.
authors.forename: R F
authors.initials: RF
authors.lastname: Hoffmann
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Suite 800, Toronto, ON M5G 0A3, Canada; Department of Pharmacology & Toxicology, University of Toronto, 101 College Street, Suite 800, Toronto, ON M5G 0A3, Canada. Electronic address: paul.boutros@oicr.on.ca.
authors.forename: P C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Department of Clinical Genomics, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: bert.smeets@maastrichtuniversity.nl.
authors.forename: H J M
authors.initials: HJ
authors.lastname: Smeets
authors.affiliation: Department of Radiation Oncology (MaastRO) Lab, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: ludwig.dubois@maastrichtuniversity.nl.
authors.forename: L
authors.initials: L
authors.lastname: Dubois
authors.affiliation: Department of Radiation Oncology (MaastRO) Lab, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, PO Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: philippe.lambin@maastro.nl.
authors.forename: P
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D057285:Precision Medicine; D011836:Radiation Tolerance
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins
keywords: Cancer; Mitochondrial DNA; Model; Mutation; OXPHOS; Variation