Mitochondrial DNA Somatic Mutations (Point Mutations and Large Deletions) and Mitochondrial DNA Variants in Human Thyroid Pathology

Abstract

In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of non-silent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion's histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors.

Lack of complex I is associated with oncocytic thyroid tumours

“…An association between mitochondrial DNA (mtDNA) mutations and oncocytic thyroid tumours was reported in several studies (Tallini et al, 1994;Maximo et al, 2002;Bonora et al, 2006). A study on 45 oncocytic thyroid tumours identified potentially pathogenic mutations in subunits of complex I (NADH-ubiquinone oxidoreductase) in 53% of the investigated samples (Gasparre et al, 2007).…”

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

“…In particular, deficient complex I activity has been described in renal oncocytoma (15,16), and a correlation between mitochondrial hyperplasia and tumorigenesis has been suggested (17). Most mtDNA changes reported in thyroid oncocytic tumors have been identified after partial sequencing of the mitochondrial genome, again without proven pathogenicity (18,19). To the best of our knowledge, a systematic approach with complete sequencing of the whole mtDNA from tumor samples and strict mitochondrial genotypephenotype correlation has not been carried out.…”

Hurthle Cell Tumours of the Thyroid- Personal Experience with Review of the Literature

“…The pathogenesis of these lesions seems related to alterations of mitochondrial DNA (mtDNA) 39 . Systematic analysis of the primary structure of mtDNA in 79 benign and malignant tumours (43 Hurthle and 36 non-Hurthle cell neoplasms) and respective normal parenchyma displayed a relatively high percentage (up to 16%) of mtDNA common deletions (CD) in Hurthle cell tumours, irrespective of the histology of the lesion.…”