A mutation screening of oncogenes, tumor suppressor gene TP53 and nuclear encoded mitochondrial complex I genes in oncocytic thyroid tumors.

摘要

Background: Thyroid neoplasias with oncocytic features represent a specific phenotype in non-medullary thyroidudcancer, reflecting the unique biological phenomenon of mitochondrial hyperplasia in the cytoplasm. Oncocyticudthyroid cells are characterized by a prominent eosinophilia (or oxyphilia) caused by mitochondrial abundance.udAlthough disruptive mutations in the mitochondrial DNA (mtDNA) are the most significant hallmark of such tumors,udoncocytomas may be envisioned as heterogeneous neoplasms, characterized by multiple nuclear and mitochondrialudgene lesions. We investigated the nuclear mutational profile of oncocytic tumors to pinpoint the mutations that mayudtrigger the early oncogenic hit.udMethods: Total DNA was extracted from paraffin-embedded tissues from 45 biopsies of oncocytic tumors.udHigh-resolution melting was used for mutation screening of mitochondrial complex I subunits genes. Specificudnuclear rearrangements were investigated by RT-PCR (RET/PTC) or on isolated nuclei by interphase FISH (PAX8/PPARγ).udRecurrent point mutations were analyzed by direct sequencing.udResults: In our oncocytic tumor samples, we identified rare TP53 mutations. The series of analyzed cases did notudinclude poorly- or undifferentiated thyroid carcinomas, and none of the TP53 mutated cases had significant mitoticudactivity or high-grade features. Thus, the presence of disruptive TP53 mutations was completely unexpected. In addition,udnovel mutations in nuclear-encoded complex I genes were identified.udConclusions: These findings suggest that nuclear genetic lesions altering the bioenergetics competence of thyroid cellsudmay give rise to an aberrant mitochondria-centered compensatory mechanism and ultimately to the oncocytic phenotype.udKeywords: Oncocytic carcinoma, Nuclear mitochondrial complex I subunits, Oncogene mutation analysis