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.

Download full-text


Available from: Luisa Iommarini
  • Source
    • "two or more independent laboratories (Lott et al. 2013), and 25 clearly pathogenic cancer-associated mutations (Gasparre et al. 2007; Porcelli et al. 2010; Pereira et al. 2012), was used to define the 'disease score' (as described in the " Results " section 'Disease Score definition') of any non-synonymous mtDNA variants, by weighting the 6 above-listed pathogenicity predictions (Thomas and Kejariwal 2004; Adzhubei et al. 2013; Capriotti et al. 2013) available in the 'patho_table' implemented in MToolBox ( mtoolbox/). These six methods were chosen among the most widely used pathogenicity predictors, available online for a fast evaluation of large-scale data from sequencing, although their often-contradictory predictions demand a way to weigh their reliability. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Assigning a pathogenic role to mitochondrial DNA (mtDNA) variants and unveiling the potential involvement of the mitochondrial genome in diseases are challenging tasks in human medicine. Assuming that rare variants are more likely to be damaging, we designed a phylogeny-based prioritization workflow to obtain a reliable pool of candidate variants for further investigations. The prioritization workflow relies on an exhaustive functional annotation through the mtDNA extraction pipeline MToolBox and includes Macro Haplogroup Consensus Sequences to filter out fixed evolutionary variants and report rare or private variants, the nucleotide variability as reported in HmtDB and the disease score based on several predictors of pathogenicity for non-synonymous variants. Cutoffs for both the disease score as well as for the nucleotide variability index were established with the aim to discriminate sequence variants contributing to defective phenotypes. The workflow was validated on mitochondrial sequences from Leber's Hereditary Optic Neuropathy affected individuals, successfully identifying 23 variants including the majority of the known causative ones. The application of the prioritization workflow to cancer datasets allowed to trim down the number of candidate for subsequent functional analyses, unveiling among these a high percentage of somatic variants. Prioritization criteria were implemented in both standalone ( ) and web version ( ) of MToolBox.
    Full-text · Article · Nov 2015 · Human Genetics
    • "In a variety of such oncocytic tumors, respiratory chain complex I is either undetectable or greatly reduced, whereas the levels of the other OXPHOS complexes are elevated. In about half of the oncocytoma cases, complex I deficiency was caused by loss-offunction mutations in complex I subunits encoded by the mitochondrial genome (mtDNA) (Gasparre et al., 2007, 2008, 2009; Mayr et al., 2008; Simonnet et al., 2003; Zimmermann et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncocytic cells (OCs) are characterized by an accumulation of mitochondria and their occurrence in the thyroid gland of patients with Hashimoto thyroiditis (HT) is well known. However, their properties and functional relevance are poorly understood. We investigated OC lesions (n=212) in the thyroid of 12 HT patients. Loss of complex I protein was observed in oncocytic lesions of each of the patients. In addition to isolated complex I deficiency, 25% of oncocytic lesions show combined deficiency of complex I and IV. Thus, we demonstrate for the first time a defect of respiratory chain complex I in OCs of HT patients.
    No preview · Article · Nov 2015 · Mitochondrion
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    No preview · Article · Aug 2015 · American Journal of Cancer Research
Show more