Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours

Yeh, Jen Jen; Lunetta, Kathryn L.; Orsouw, Nathalie J. van; Moore, Francis D.; Mutter, George L.; Vijg, Jan; Dahia, Patricia L.M.; Eng, Charis

doi:10.1038/sj.onc.1203537

Cited by 151 publications

(134 citation statements)

References 17 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Several authors have performed gene expression and biochemical studies to investigate molecular aspects of this specific histological phenotype (13,14). 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).…”

mentioning

confidence: 99%

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

Gasparre

Porcelli²,

Bonora

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

259

215

View full text Add to dashboard Cite

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.oncocytic tumors ͉ heteroplasmy ͉ homoplasmy ͉ damaging mutation ͉ microenvironment

show abstract

mentioning

confidence: 99%

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

Gasparre

Porcelli²,

Bonora

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

259

215

View full text Add to dashboard Cite

show abstract

“…Cavalli et al (1997) found diminished tumor formation by glioblastoma cells following depletion of mtDNA (r 0 cells) with ethidium bromide treatment, while Morais et al (1994) found increased capacity to proliferate and form tumors in vivo by ovarian, and cervical carcinoma cells and osteosarcoma cells following mtDNA depletion. Recently, wide range of tumors have been shown to contain both heteroplasmic and homoplasmic mutations as well as deletions in their mtDNA (Horton et al, 1996;Polyak et al, 1998;Fliss et al, 2000;Yeh et al, 2000). Since the genes involved in tumorigenicity are largely nuclear encoded, one wonders if damage to mtDNA somehow helps activate nuclear oncogenes; or if induced mutations and altered mitochondrial functions are the consequence of the carcinogenic processes, but not contributing factors.…”

mentioning

confidence: 99%

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Amuthan

Biswas

Ananadatheerthavarada

et al. 2002

Oncogene

228

271

View full text Add to dashboard Cite

We have investigated mechanisms of mitochondrial stressinduced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca 2+ ] c , and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFb1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X L were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFb1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondriato-nucleus signaling pathway operating through increased [Ca 2+ ] c plays an important role in cancer progression and metastasis. Oncogene (2002Oncogene ( ) 21, 7839 -7849. doi:10.1038 Keywords: mitochondria; calcium signaling; cathepsin L; TGFb; tumor invasion; MAP kinases IntroductionThe role of mitochondria in carcinogenesis was initially suggested by Warburg et al. (1926;Warburg, 1956), based on the observation that number of experimentally induced rodent tumors exhibit reduced respiration-coupled oxidative metabolism and increased glycolysis. Since then, altered mitochondrial morphology, as well as changes in mitochondrial enzyme patterns and membrane transport systems, have been described in several tumor types (Zafar et al., 1982). Cell fusion studies (Jonasson et al., 1977;Howell and Sager, 1978;Giguere and Morais, 1981) also suggest that unknown cytoplasmic elements may play roles in carcinogenesis. Fusion between normal cytoplasm and karyoplasts from malignant phenotypes resulted in the ablation of tumorigenicity (Israel and Schaeffer, 1987) and conversely, the cytoplasm of the malignant phenotype could transfer the malignancy to the karyoplasts from normal cells (Israel and Schaeffer, 1988). Studies using mitochondrial DNA (mtDNA)-depleted tumor cells to evaluate the role of mtDNA, and thus mitochondrial function in tumorigenicity have yielded mixed results (Giguere and Morais, 1981;Morais et al., 1994;Cavalli et al., 1997;Cavalli and Liang, 1998;Hofhaus and Gattermann, 1999). Cavalli et al. (1997) found diminished tumor formation by glioblastoma cells following depletion of mtDNA (r 0 cells) with ethidium bromide treatment, while Morais et al. (1994) found increased capacity to p...

show abstract

“…Its role in apoptosis supports this hypothesis (Zamzami and Kroemer, 2001) and it was shown that mtDNA mutations may lead to a dysregulation of oxidative phosphorylation that can enhance production of the carcinogenic ROS. Over last years, somatic mtDNA mutations have been reported in many human tumours (Polyak et al, 1998;Maximo et al, 2000;Richard et al, 2000;Yeh et al, 2000;Hibi et al, 2001b;Sanchez-Cespedes et al, 2001;Kirches et al, 2001;Liu et al, 2001;Lievre et al, 2005), including head and neck squamous cell carcinoma (HNSCC) that were found mutated in small series in 37 -77% of the cases (Fliss et al, 2000;Sanchez-Cespedes et al, 2001;Ha et al, 2002;Tan et al, 2003;Poetsch et al, 2004). Although mutations may occur throughout the mitochondrial genome, the vast majority of them have been described in the noncoding region of the D-Loop and particularly in a mononucleotide repeat named D310 (C-tract, nucleotide position: 303 -315) that has emerged as a mutational hotspot in HNSCC (Fliss et al, 2000;Sanchez-Cespedes et al, 2001;Ha et al, 2002;Tan et al, 2003;Poetsch et al, 2004).…”

mentioning

confidence: 99%

Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

et al. 2006

View full text Add to dashboard Cite

Mitochondrial DNA mutations have been reported in several types of tumours, including head and neck squamous cell carcinoma (HNSCC). The noncoding region of the Displacement-Loop (D-Loop) has emerged as a mutational hotspot and we recently found that they were associated with prognosis and response to 5 fluorouracil (5FU) in colon cancers. In order to evaluate the frequence of D-Loop mutations in a large series of HNSCC and establish correlations with clinicopathologic parameters, we sequenced the D-Loop of 109 HNSCC before a treatment by neoadjuvant 5FU-cisplatin-based chemotherapy and surgery. Then, we correlated these mutations with prognosis and response to chemotherapy. A D-Loop mutation was identified in 21% of the tumors, the majority of them were located in a C-tract (D310). The prevalence of D310 mutations increased significantly with the number of cytosines in the matched normal tissue sequence (P ¼ 0.02). Hypopharyngeal cancer was significantly more frequent (P ¼ 0.03) and tobacco consumption more important (P ¼ 0.01) in the group of patients with D-Loop mutation. The presence of D-Loop mutation was not associated with prognosis or with response to neoadjuvant chemotherapy. These results suggest that D-Loop mutations should be considered as a cancer biomarker that may be useful for the early detection of HNSCC in individuals at risk of this cancer.

show abstract

Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours

Cited by 151 publications

References 17 publications

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

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

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

Contact Info

Product

Resources

About