Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, University of Bologna, 40126 Bologna, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2007; 104(21):9001-6. DOI: 10.1073/pnas.0703056104
Source: PubMed


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.

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    • "Sequencing of the entire mtDNA was performed according to standard, previously published protocols in 2 cases (OT9 e OT10). In the remaining cases the status of mtDNA had been previously characterized and reported [5]. Among the samples analyzed, 2/14 oncocytic and 5/12 non-oncocytic samples are novel and are described here for the first time. "
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    ABSTRACT: Oncocytic change is the result of aberrant mitochondrial hyperplasia, which may occur in both neoplastic and non-neoplastic cells and is not infrequent in the thyroid. Despite being a well-characterized histologic phenotype, the molecular causes underlying such a distinctive cellular change are poorly understood. To identify potential genetic causes for the oncocytic phenotype in thyroid, we analyzed copy number alterations in a set of oncocytic (n=21) and non-oncocytic (n=20) thyroid lesions by high-resolution microarray-based comparative genomic hybridization (aCGH). Each group comprised lesions of diverse histologic types, including hyperplastic nodules, adenomas and carcinomas. Unsupervised hierarchical clustering of categorical aCGH data resulted in two distinct branches, one of which was significantly enriched for samples with the oncocytic phenotype, regardless of histologic type. Analysis of aCGH events showed that the oncocytic group harbored a significantly higher number of genes involved in copy number gains, when compared to that of conventional thyroid lesions. Functional annotation demonstrated an enrichment for copy number gains that affect genes encoding activators of mitochondrial biogenesis in oncocytic cases but not in their non-oncocytic counterparts. Taken together, our data suggest that genomic alterations may represent additional/alternative mechanisms underlying the development of the oncocytic phenotype in the thyroid.
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    • "All variable positions were used except 16182C, 16183C, and 16519, as they are inconsistently reported in the literature and are too recurrent. We also used 18 previously published whole HV1 genome sequences [AY738942 and AY738943 (Achilli et al., 2004), EF556168, EF556182, and EF556190 (Behar et al., 2008), FJ460547 (Costa et al., 2009), EF660935 and EF660936 (Gasparre et al., 2007), EU935461 (Kujanová et al., 2009), FJ210914, EF421157 "

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    • "This suggests that the relatively higher mtDNA content in CA prostate cancer patients could cause accumulation of abundant but morphologically altered mitochondria, which may induce apoptosis or alternate forms of programmed cancer cell death in prostate tumors. These findings are consistent with earlier reports that increased mtDNA mutations in thyroid tumors induce accumulation of defective and altered mitochondria [45], [46]. The exact mechanism of decreased mtDNA content in tumors from AA men as well as the relatively higher mtDNA content in CA men is unknown, but because cancer development is influenced by external and environmental factors in addition to genetic factors, both factors might be playing a role in the differential expression of mtDNA in normal prostate epithelial tissues and tumors from these two populations. "
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    ABSTRACT: Reduction or depletion of mitochondrial DNA (mtDNA) has been associated with cancer progression. Although imbalanced mtDNA content is known to occur in prostate cancer, differences in mtDNA content between African American (AA) and Caucasian American (CA) men are not defined. We provide the first evidence that tumors in AA men possess reduced level of mtDNA compared to CA men. The median tumor mtDNA content was reduced in AA men. mtDNA content was also reduced in normal prostate tissues of AA men compared to CA men, suggesting a possible predisposition to cancer in AA men. mtDNA content was also reduced in benign prostatic hyperplasia (BPH) tissue from AA men. Tumor and BPH tissues from patients ≥60 years of age possess reduced mtDNA content compared to patients <60 years of age. In addition, mtDNA content was higher in normal tissues from patients with malignant T3 stage disease compared to patients with T2 stage disease. mtDNA levels in matched normal prostate tissues were nearly doubled in Gleason grade of >7 compared to ≤7, whereas reduced mtDNA content was observed in tumors of Gleason grade >7 compared to ≤7. Together, our data suggest that AA men possess lower mtDNA levels in normal and tumor tissues compared to CA men, which could contribute to higher risk and more aggressive prostate cancer in AA men.
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