Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors.
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.
Gasparre
Giuseppe
G
Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, University of Bologna, 40126 Bologna, Italy.
Porcelli
Anna Maria
AM
Bonora
Elena
E
Pennisi
Lucia Fiammetta
LF
Toller
Matteo
M
Iommarini
Luisa
L
Ghelli
Anna
A
Moretti
Massimo
M
Betts
Christine M
CM
Martinelli
Giuseppe Nicola
GN
Ceroni
Alberto Rinaldi
AR
Curcio
Francesco
F
Carelli
Valerio
V
Rugolo
Michela
M
Tallini
Giovanni
G
Romeo
Giovanni
G
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
D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D021122:Protein Subunits; D042967:Electron Transport Complex I