Lack of complex I is associated with oncocytic thyroid tumours

Zimmermann, Franz; Mayr, Johannes A.; Neureiter, Daniel; Feichtinger, René G.; Alinger, Beate; Jones, Neil D.; Eder, Waltraud; Sperl, Wolfgang; Kofler, Barbara

doi:10.1038/sj.bjc.6605028

Cited by 59 publications

(73 citation statements)

References 16 publications

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“…They occur both in the 'C' tract of the D-loop region and in all the 13 genes that encode OXPHOS proteins, being more frequent in complex I genes than in the genes of the other complexes (Máximo et al 2002, 2005b, Gasparre et al 2007, Zimmermann et al 2009). Occasionally, mutations in some tRNAs have also been detected (Máximo et al 2002).…”

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

“…Hürthle cell tumors differ from their non-Hürthle cell counterparts regarding the prevalence of alterations in mtDNA genes and in nuclear genes (nuclear DNA (nDNA)) coding for mitochondrial proteins (Máximo et al 2002, 2005a, Abu-Amero et al 2005, Bonora et al 2006b, Gasparre et al 2007, Zimmermann et al 2009). …”

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

“…The OXPHOS gene mutations include frameshift and both silent and missense point mutations. Disruptive mutations (either frameshift or nonsense) tend to be concentrated in complex I genes, without any apparent concentration in a single gene (Máximo et al 2002, Gasparre et al 2007, Zimmermann et al 2009). Immunohistochemical analyses of Hürthle cell FTCs have confirmed a specific lack of complex I, which was expressed at !5% of the level in surrounding nontumoral tissue (Zimmermann et al 2009).…”

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

“…Disruptive mutations (either frameshift or nonsense) tend to be concentrated in complex I genes, without any apparent concentration in a single gene (Máximo et al 2002, Gasparre et al 2007, Zimmermann et al 2009). Immunohistochemical analyses of Hürthle cell FTCs have confirmed a specific lack of complex I, which was expressed at !5% of the level in surrounding nontumoral tissue (Zimmermann et al 2009). Gasparre et al (2007) found that the only breast carcinoma of their series that presented an mtDNA complex I gene mutation was a mitochondrion-rich carcinoma, thus reinforcing the association between disruptive mtDNA complex I mutations and the occurrence of Hürthle cell phenotype.…”

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

“…Interestingly, lack of complex I has been proposed to prevent tumor cells from undergoing apoptosis (Zimmermann et al 2009). The data on mtDNA and nDNA mutations in Hürthle cell tumors are summarized in Table 2.…”

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

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The biology and the genetics of Hürthle cell tumors of the thyroid

Máximo¹,

Lima²,

Prazeres³

et al. 2012

Endocrine-Related Cancer

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The biology and the genetics of Hü rthle cell tumors are reviewed starting from the characterization and differential diagnosis of the numerous benign and malignant, neoplastic and nonneoplastic lesions of the thyroid in which Hü rthle cell transformation is frequently observed. The clinicopathologic and molecular evidence obtained from the comparative study of the aforementioned conditions indicate that Hü rthle cell appearance represents a phenotype that is superimposed on the genotypic and conventional histopathologic features of the tumors. Hürthle cell tumors differ from their non-Hü rthle counterparts regarding the prevalence of large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins (namely mutations of complex I subunit genes) and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins. Such mitochondrial alterations lead to energy production defects in Hü rthle cell tumors; the increased proliferation of mitochondria may reflect a compensatory mechanism for such defects and is associated with the overexpression of factors involved in mitochondrial biogenesis. The mitochondrial abnormalities are also thought to play a major role in the predisposition for necrosis instead of apoptosis which seems to be blocked in most Hü rthle cell tumors. Finally, the results obtained in experimental models using cybrid cell lines and the data obtained from histopathologic and molecular studies of familial Hü rthle cell tumors are used, together with the aforementioned genetic and epigenetic alterations, to progress in the understanding of the mechanisms through which mitochondrial abnormalities may be involved in the different steps of thyroid carcinogenesis, from tumor initiation to metastization.

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Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

Section: Mtdna Encoded Mitochondrial Genes Alterations In Hü Rthle Cementioning

confidence: 99%

See 3 more Smart Citations

The biology and the genetics of Hürthle cell tumors of the thyroid

Máximo¹,

Lima²,

Prazeres³

et al. 2012

Endocrine-Related Cancer

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Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors

Tsybrovskyy

Luise

Biase

et al. 2021

The Journal of Pathology CR

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Papillary thyroid carcinoma tall cell variant (PTC-TCV), a form of PTC regarded as an aggressive subtype, shares several morphologic features with oncocytic tumors. Pathogenic homoplasmic/highly heteroplasmic somatic mitochondrial DNA (mtDNA) mutations, usually affecting oxidative phosphorylation (OXPHOS) complex I subunits, are hallmarks of oncocytic cells. To clarify the relationship between PTC-TCV and oncocytic thyroid tumors, 17 PTC-TCV and 16 PTC non-TCV controls (cPTC) were subjected to: (1) transmission electron microscopy (TEM) to assess mitochondria accumulation, (2) next-generation sequencing to analyze mtDNA and nuclear genes frequently mutated in thyroid carcinoma, and (3) immunohistochemistry (IHC) for prohibitin and complex I subunit NDUFS4 to evaluate OXPHOS integrity. TEM showed replacement of cytoplasm by mitochondria in PTC-TCV but not in cPTC cells. All 17 PTC-TCV had at least one mtDNA mutation, totaling 21 mutations; 3/16 cPTC (19%) had mtDNA mutations (p < 0.001). PTC-TCV mtDNA mutations were homoplasmic/highly heteroplasmic, 16/21 (76%) mapping within mtDNA-encoded complex I subunits. MtDNA mutations in cPTC were homoplasmic in 2 cases and at low heteroplasmy in the third case, 2/3 mapping to mtDNA-encoded complex I subunits; 2/3 cPTC with mtDNA mutations had small tall cell subpopulations. PTC-TCV showed strong prohibitin expression and cPTC low-level expression, consistent with massive and limited mitochondrial content, respectively. All 17 PTC-TCV showed NDUFS4 loss (partial or complete) and 3 of 16 cPTC (19%) had (partial) NDUFS4 loss, consistent with lack of complex I integrity in PTC-TCV (p < 0.001). IHC loss of NDUFS4 was associated with mtDNA mutations (p < 0.001). Four BRAF V600E mutated PTCs had loss of NDUSF4 expression limited to neoplastic cell subpopulations with tall cell features, indicating that PTCs first acquire BRAF V600E and then mtDNA mutations. Similar to oncocytic thyroid tumors, PTC-TCV is characterized by mtDNA mutations, massive accumulation of mitochondria, and loss of OXPHOS integrity. IHC loss of NDUFS-4 can be used as a surrogate marker for OXPHOS disruption and to reliably diagnose PTC-TCV.

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Near‐haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations

Corver

Wezel

Molenaar

et al. 2014

Genes Chromosomes & Cancer

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Mitochondrial-rich oncocytic thyroid tumors frequently show near-haploidization and endoreduplication (masked haploidization), which manifests as a near-homozygous genome (NHG). We now extend this investigation to include adrenocortical cancer and parathyroid carcinoma (PaTC), which we studied for a NHG in association with mitochondrial DNA mutations. Sixty endocrine tumors from 59 patients were studied, including 46 thyroid tumor samples of varying histology, 11 adrenocortical cancers, and 3 PaTCs. Genome-wide SNP array analysis and DNA content analysis were combined to determine the chromosomal dosage (allelic state). The entire mitochondrial genome was also studied for mutations. In addition, tumors were characterized for somatic mutations in a subset of genes that are directly or indirectly implicated in cellular metabolism. In addition to a subset of thyroid cancers (n = 5), a NHG was also observed in 1 of 3 PaTCs and 6 of 11 adrenocortical cancers. All but one of the tumors with a NHG (n = 12) showed oncocytic metaplasia (P = 0.0001, two-tailed Fisher's exact). One or more damaging or disrupting mtDNA mutations were found in 68% (41/60) of tumor samples. No correlation was found between mtDNA mutations and the oncocytic phenotype or a NHG, and none of the mutations in nuclear encoded genes correlated with the oncocytic phenotype or a NHG. A subset of oncocytic tumors of the thyroid, parathyroid, and adrenocortical carcinomas carries a NHG. Although damaging/disrupting mtDNA mutations are frequently found in oncocytic and nononcocytic endocrine tumors, neither correlates with a NHG phenotype nor with an oncocytic phenotype.

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Lack of complex I is associated with oncocytic thyroid tumours

Cited by 59 publications

References 16 publications

The biology and the genetics of Hürthle cell tumors of the thyroid

The biology and the genetics of Hürthle cell tumors of the thyroid

Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors

Near‐haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations

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