title: Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort.
abstract: It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.
authors.affiliation: Institute for Risk Assessment Sciences, Division Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands; Zanjan University of Medical Sciences, Zanjan, Iran;
authors.forename: Fatemeh Saberi
authors.initials: FS
authors.lastname: Hosnijeh
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD;
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD;
authors.forename: Nathaniel
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authors.lastname: Rothman
authors.affiliation: Department of Neurology and Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan;
authors.forename: Chin
authors.initials: C
authors.lastname: San Liu
authors.affiliation: Laboratory of Mitochondrial Medicine, Chunghua Christian Hospital, Taipei, Taiwan;
authors.forename: Wen-Ling
authors.initials: WL
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authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Centre Freiburg, Freiburg, Germany;
authors.forename: Alexandra
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authors.lastname: Nieters
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark;
authors.forename: Per
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authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark;
authors.forename: Anne
authors.initials: A
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authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Daniele
authors.initials: D
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authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Alessandro
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authors.lastname: Martino
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany;
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.affiliation: Hellenic Health Foundation, Athens, Greece; WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece;
authors.forename: Antonia
authors.initials: A
authors.lastname: Trichopoulou
authors.affiliation: WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece; Department of Epidemiology, Harvard School of Public Health, Boston, MA; Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece;
authors.forename: Pagona
authors.initials: P
authors.lastname: Lagiou
authors.affiliation: Hellenic Health Foundation, Athens, Greece; Department of Epidemiology, Harvard School of Public Health, Boston, MA; Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece;
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;
authors.forename: Vittorio
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authors.affiliation: Cancer Registry and Histopathology Unit, "Civic - M.P. Arezzo" Hospital, ASP Ragusa, Italy;
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy;
authors.forename: Salvatore
authors.initials: S
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authors.affiliation: Molecular and Nutritional Epidemiology Unit, ISPO Cancer Research and Prevention Institute, Florence, Italy;
authors.forename: Giovanna
authors.initials: G
authors.lastname: Masala
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway; Department of Research, Cancer Registry of Norway, Oslo, Norway; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Samfundet Folkhälsan, Helsinki, Finland;
authors.forename: Elisabete
authors.initials: E
authors.lastname: Weiderpass
authors.affiliation: Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain; CIBER Epidemiology and Public Health CIBERESP, Spain;
authors.forename: José María
authors.initials: JM
authors.lastname: Huerta Castaño
authors.affiliation: CIBER Epidemiology and Public Health CIBERESP, Spain; Navarre Public Health Institute, Pamplona, Spain;
authors.forename: Eva
authors.initials: E
authors.lastname: Ardanaz
authors.affiliation: Translational Research Laboratory and Unit of Nutrition, Environment and Cancer Research Program in Cancer Epidemiology, Catalan Institute of Oncology, Biomedical Research Institute (IDIBELL), Barcelona, Spain;
authors.forename: Núria
authors.initials: N
authors.lastname: Sala
authors.affiliation: Public Health Direction and Biodonostia Research Institute Ciberesp, Basque Regional Health Department, Vitoria, Spain;
authors.forename: Miren
authors.initials: M
authors.lastname: Dorronsoro
authors.affiliation: Public Health Directorate, Asturias, Spain;
authors.forename: J Ramón
authors.initials: JR
authors.lastname: Quirós
authors.affiliation: CIBER Epidemiology and Public Health CIBERESP, Spain; Andalusian School of Public Health, Granada, Spain; Instituto de Investigación Biosanitario de Granada, Granada, Spain;
authors.forename: María-José
authors.initials: MJ
authors.lastname: Sánchez
authors.affiliation: Department of Radiation Sciences, Oncology Umeå University, Umeå, Sweden;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Melin
authors.affiliation: Department of Radiation Sciences, Oncology Umeå University, Umeå, Sweden;
authors.forename: Ann Sofie
authors.initials: AS
authors.lastname: Johansson
authors.affiliation: Department of Laboratory Medicine, Clinical Chemistry, Lund University, Malmö, Sweden; Skåne University Hospital, Malmö, Sweden;
authors.forename: Johan
authors.initials: J
authors.lastname: Malm
authors.affiliation: Division of Oncology, Department of Clinical Sciences, Lund University, Malmö, Sweden;
authors.forename: Signe
authors.initials: S
authors.lastname: Borgquist
authors.affiliation: Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht;
authors.forename: Petra H
authors.initials: PH
authors.lastname: Peeters
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; The School of Public Health, Imperial College London, London, United Kingdom;
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Nick
authors.initials: N
authors.lastname: Wareham
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom;
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.affiliation: Genetics Section, International Agency for Research on Cancer, Lyon, France;
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom;
authors.forename: Afshan
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; and.
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.affiliation: The School of Public Health, Imperial College London, London, United Kingdom; Human Genetics Foundation, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Institute for Risk Assessment Sciences, Division Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht;
authors.forename: Roel
authors.initials: R
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mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D004272:DNA, Mitochondrial