title: A mutation screening of oncogenes, tumor suppressor gene TP53 and nuclear encoded mitochondrial complex I genes in oncocytic thyroid tumors.
abstract: BACKGROUND
  Thyroid neoplasias with oncocytic features represent a specific phenotype in non-medullary thyroid cancer, reflecting the unique biological phenomenon of mitochondrial hyperplasia in the cytoplasm. Oncocytic thyroid cells are characterized by a prominent eosinophilia (or oxyphilia) caused by mitochondrial abundance. Although disruptive mutations in the mitochondrial DNA (mtDNA) are the most significant hallmark of such tumors, oncocytomas may be envisioned as heterogeneous neoplasms, characterized by multiple nuclear and mitochondrial gene lesions. We investigated the nuclear mutational profile of oncocytic tumors to pinpoint the mutations that may trigger the early oncogenic hit.
  
  
  METHODS
  Total DNA was extracted from paraffin-embedded tissues from 45 biopsies of oncocytic tumors. High-resolution melting was used for mutation screening of mitochondrial complex I subunits genes. Specific nuclear rearrangements were investigated by RT-PCR (RET/PTC) or on isolated nuclei by interphase FISH (PAX8/PPARγ). Recurrent point mutations were analyzed by direct sequencing.
  
  
  RESULTS
  In our oncocytic tumor samples, we identified rare TP53 mutations. The series of analyzed cases did not include poorly- or undifferentiated thyroid carcinomas, and none of the TP53 mutated cases had significant mitotic activity or high-grade features. Thus, the presence of disruptive TP53 mutations was completely unexpected. In addition, novel mutations in nuclear-encoded complex I genes were identified.
  
  
  CONCLUSIONS
  These findings suggest that nuclear genetic lesions altering the bioenergetics competence of thyroid cells may give rise to an aberrant mitochondria-centered compensatory mechanism and ultimately to the oncocytic phenotype.
authors.affiliation: Department of Medical and Surgical Sciences (DIMEC), Policlinico S. Orsola-Malpighi, Unit of Medical Genetics, University of Bologna, Bologna, Italy. cecilia.evangelisti2@unibo.it.|Department of Biomedical and Neuromotor Sciences (DIBINEM), Cell Signaling Laboratory, University of Bologna, Bologna, Italy. cecilia.evangelisti2@unibo.it.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Department of Diagnostic, Experimental and Specialty Medicine (DIMES), Unit of Anatomic Pathology, Bellaria Hospital, University of Bologna, Bologna, Italy. dario.debiase@unibo.it.
authors.forename: Dario
authors.initials: D
authors.lastname: de Biase
authors.affiliation: Department of Medical and Surgical Sciences (DIMEC), Policlinico S. Orsola-Malpighi, Unit of Medical Genetics, University of Bologna, Bologna, Italy. ivana_kurelac@yahoo.com.
authors.forename: Ivana
authors.initials: I
authors.lastname: Kurelac
authors.affiliation: Department of Diagnostic, Experimental and Specialty Medicine (DIMES), Unit of Anatomy, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy. claudio.ceccarelli@unibo.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.affiliation: Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany. Prokisch@helmholtz-muenchen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany. meitinger@helmholtz-muenchen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. paola.caria@unibo.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Caria
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. vanni@unica.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Vanni
authors.affiliation: Department of Medical and Surgical Sciences (DIMEC), Policlinico S. Orsola-Malpighi, Unit of Medical Genetics, University of Bologna, Bologna, Italy. egf.giovanni.romeo@gmail.com.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.affiliation: Department of Diagnostic, Experimental and Specialty Medicine (DIMES), Unit of Anatomic Pathology, Bellaria Hospital, University of Bologna, Bologna, Italy. giovanni.tallini@unibo.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.affiliation: Department of Medical and Surgical Sciences (DIMEC), Policlinico S. Orsola-Malpighi, Unit of Medical Genetics, University of Bologna, Bologna, Italy. giuseppe.gasparre@gmail.com.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.affiliation: Department of Medical and Surgical Sciences (DIMEC), Policlinico S. Orsola-Malpighi, Unit of Medical Genetics, University of Bologna, Bologna, Italy. elena.bonora6@unibo.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
mesh_terms: D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D064351:Genes, Microbial; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006801:Humans; D009154:Mutation; D009857:Oncogenes; D011995:Recombination, Genetic; D013964:Thyroid Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D042967:Electron Transport Complex I