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: 9.81). 06/2007; 104(21):9001-6. DOI: 10.1073/pnas.0703056104
Source: PubMed

ABSTRACT 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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Available from: Luisa Iommarini, Sep 03, 2015
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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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    • "MtDNA sequences were then used to construct a phylogenetic network separately for the coding region (Figure 1) and the D-loop (Figure 2). Exact test of population differentiation [38] revealed no differences in the frequencies of mtDNA haplogroups between patients and controls (Table 1). "
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