Mitochondrial DNA copy number variation, leukocyte telomere length, and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Abstract

open21siThe coordination of the EPIC study is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the following organizations: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) (PI13/00061 to Granada, PI13/01162 to EPIC-Murcia), the regional Governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, and Instituto de Salud Carlos III (ISCIII) Redes temáticas de investigación cooperativa en salud (RETICS) (RD06/0020) (Spain); and Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford) and the Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United KingdomBackground: Leukocyte telomere length (LTL) and mitochondrial genome (mtDNA) copy number and deletions have been proposed as risk markers for various cancer types, including breast cancer (BC). Methods: To gain a more comprehensive picture on how these markers can modulate BC risk, alone or in conjunction, we performed simultaneous measurements of LTL and mtDNA copy number in up to 570 BC cases and 538 controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. As a first step, we measured LTL and mtDNA copy number in 96 individuals for which a blood sample had been collected twice with an interval of 15 years. Results: According to the intraclass correlation (ICC), we found very good stability over the time period for both measurements, with ICCs of 0.63 for LTL and 0.60 for mtDNA copy number. In the analysis of the entire study sample, we observed that longer LTL was strongly associated with increased risk of BC (OR 2.71, 95% CI 1.58-4.65, p = 3.07 × 10-4 for highest vs. lowest quartile, OR 3.20, 95% CI 1.57-6.55, p = 1.41 × 10-3 as a continuous variable). We did not find any association between mtDNA copy number and BC risk; however, when considering only the functional copies, we observed an increased risk of developing estrogen receptor-positive BC (OR 2.47, 95% CI 1.05-5.80, p = 0.04 for highest vs. lowest quartile). Conclusions: We observed a very good correlation between the markers over a period of 15 years. We confirm a role of LTL in BC carcinogenesis and suggest an effect of mtDNA copy number on BC risk.openCampa, Daniele; Barrdahl, Myrto; Santoro, Aurelia; Severi, Gianluca; Baglietto, Laura; Omichessan, Hanane; Tumino, Rosario; Bueno-de-Mesquita, H.B(as).; Peeters, Petra H.; Weiderpass, Elisabete; Chirlaque, Maria-Dolores; Rodríguez-Barranco, Miguel; Agudo, Antonio; Gunter, Marc; Dossus, Laure; Krogh, Vittorio; Matullo, Giuseppe; Trichopoulou, Antonia; Travis, Ruth C.; Canzian, Federico; Kaaks, Rudolf*Campa, Daniele; Barrdahl, Myrto; Santoro, Aurelia; Severi, Gianluca; Baglietto, Laura; Omichessan, Hanane; Tumino, Rosario; Bueno-de-Mesquita, H.B(as).; Peeters, Petra H.; Weiderpass, Elisabete; Chirlaque, Maria-Dolores; Rodríguez-Barranco, Miguel; Agudo, Antonio; Gunter, Marc; Dossus, Laure; Krogh, Vittorio; Matullo, Giuseppe; Trichopoulou, Antonia; Travis, Ruth C.; Canzian, Federico; Kaaks, Rudolf