title: Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors.
abstract: Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P=0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.
authors.affiliation: Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, University of Bologna, 40126 Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.forename: Lucia Fiammetta
authors.initials: LF
authors.lastname: Pennisi
authors.forename: Matteo
authors.initials: M
authors.lastname: Toller
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Moretti
authors.forename: Christine M
authors.initials: CM
authors.lastname: Betts
authors.forename: Giuseppe Nicola
authors.initials: GN
authors.lastname: Martinelli
authors.forename: Alberto Rinaldi
authors.initials: AR
authors.lastname: Ceroni
authors.forename: Francesco
authors.initials: F
authors.lastname: Curcio
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
mesh_terms: D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D024862:Oxyphil Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D021122:Protein Subunits; D042967:Electron Transport Complex I