Human Molecular Genetics Advance Access originally published online on December 21, 2007
Human Molecular Genetics 2008 17(7):986-995; 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, Lyon F-69003, France 3 Université Lyon 1, Villeurbanne F-69100, France 4 CNRS UMR 5534, CGMC, Villeurbanne F-69100, France 5 CNRS UMR 5201, Génétique Moléculaire, Signalisation et Cancer, Lyon F-69373, France 6 Service d'Urologie 7 Laboratoire Central d'Anatomie et de Cytologie Pathologiques, Hôpital Edouard Herriot, Lyon F-69437, France 8 Nijmegen Centre for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, Nijmegen 6500 HB, The Netherlands 9 Unit of Functional Genomics, Institut Gustave Roussy, 39, rue Camille Desmoulins, Villejuif F-94805, France 10 Service de Cytogénétique, Centre Hospitalier de Chambéry, Chambéry F-73011, France
* To whom correspondence should be addressed. Tel: +33 4 78 77 70 25; Fax: +33 4 78 77 72 20; Email: simonnet{at}univ-lyon1.fr
Received November 7, 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 (CI, NADH-ubiquinone oxidoreductase). In this work total sequencing of 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 CI 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 this work.