Abstract

BackgroundThyroid 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.MethodsTotal 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.ResultsIn 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1122-3) contains supplementary material, which is available to authorized users.

Highlights

  • 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

  • A specific sub-phenotype in Non-medullary thyroid carcinoma (NMTC) is represented by thyroid tumors with oncocytic features, which reflects the unique biological phenomenon of mitochondrial

  • It is generally accepted that oncocytic tumors in the thyroid and in other organs alike should be considered as distinct subtypes, since their features are peculiar enough to set them apart from corresponding neoplasms lacking accumulation of mitochondria (World Health Organization, 2004)

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Summary

Introduction

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. Evangelisti et al BMC Cancer (2015) 15:157 hyperplasia in the cytoplasm of oncocytic cells, characterized by their prominent eosinophilia (or oxyphilia) caused by mitochondrial abundance, from where the histopathological feature of swollen (oncòs) cells originate. Among the molecular hallmarks of this phenotype, it has to be underlined that, in keeping with the observation that most of the time oncocytic cells mitochondria display a deranged morphology and function [5], disruptive mutations in the mitochondrial DNA (mtDNA) are nowadays univocally considered as the most prominent and frequent genetic signature for oncocytic tumors of the thyroid and other organs as well [6]

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