Human Molecular Genetics Advance Access first published online on December 21, 2007
This version published online on January 9, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddm371
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Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma
1 Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy 2 Université de Lyon, Villeurbanne, F-69100, France; Université Lyon 1, Villeurbanne, F-69100, France; CNRS UMR 5534, CGMC, Villeurbanne, F-69100, France. 3 Université de Lyon, Lyon, F-69008, France; Université Lyon 1, F-69008, Lyon, France, CNRS UMR 5201, Génétique Moléculaire, Signalisation et Cancer, Lyon, F-69373, France. 4 Service d'Urologie, Hôpital Edouard Herriot, F-69437 Lyon, France 5 Laboratoire Central d'Anatomie et de Cytologie Pathologiques, Hôpital Edouard Herriot, F-69437 Lyon, France 6 Nijmegen Centre for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB, Nijmegen, he Netherlands. 7 Unit of Functional Genomics, Institut Gustave Roussy, 39, rue Camille Desmoulins, F-94805 Villejuif, France. 8 Service de Cytogénétique, Centre Hospitalier de Chambéry, F-73011 Chambéry, France
* Correspondence should be sent to Hélène Simonnet, Université de Lyon, CNRS UMR 5201, Génétique Moléculaire, Signalisation et Cancer, Faculté de Médecine Grange Blanche, Lyon, F-69373, France. Tel (33) 4 78 77 70 25, Fax (33) 4 78 77 72 20. E-mail: simonnet{at}univ-lyon1.fr
Received November 7, 2007; Revised December 17, 2007; Accepted December 17, 2007
Mutations in mitochondrial DNA (mtDNA) are frequent in cancers but it is not yet clearly established whether they are modifier events involved in cancer progression or whether they are a consequence of tumorigenesis. Here we show a benign tumor type in which mtDNA mutations that lead to complex I (CI) enzyme deficiency are found in all tumors and are the only genetic alteration detected. Actually renal oncocytomas are homogeneous tumors characterized by dense accumulation of mitochondria and we had found that they are deficient in electron transport chain complex I (NADH-ubiquinone oxidoreductase). In this work total sequencing of mitochondrial DNA (mtDNA) showed that 9/9 tumors harbored point mutations in mtDNA, seven in CI genes, one in complex III, and one in the control region. 7/8 mutations were somatic. All tumors were somatically deficient for CI. The clonal amplification of mutated mtDNA in 8/9 tumors demonstrates that these alterations are selected and therefore favor or trigger growth. No nuclear DNA rearrangement was detected beside mtDNA defects. We hypothesize that functional deficiency of the oxidative phosphorylation complex I could create a loop of amplification of mitochondria during cell division, impair substrates oxidation and increase intermediary metabolites availability.
# The first three authors have contributed equally to the work
This paper has been versioned to correct the tagging of the author surname of the third author.