Mitochondrial mutations in cancer

Brandon, Martin; Baldi, Pierre; Wallace, Douglas C.

doi:10.1038/sj.onc.1209607

Cited by 730 publications

(632 citation statements)

References 84 publications

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“…2). The T16126C variant has been previously reported in breast and endometrial cancers and glioblastoma multiform [24,25]. The T16189C variant has been associated with type 2 diabetes a well as some metabolic syndrome [26,27].…”

Section: Discussionmentioning

confidence: 93%

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

Seyedhassani

Houshmand

Kalantar

et al. 2010

J Assist Reprod Genet

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Purpose Repeated pregnancy loss (RPL) occurs in 1 out of 300 couples, and the cause of about 50% of them remains idiopathic. Mitochondria have an important role in human development through ATP production and their involvement in apoptosis. Methods 96 RPL and 96 control females were used to investigate the frequency of deletions and point mutations in the displacement loop (D-loop) on mitochondria. Multiplex PCR and DNA sequencing methods were used to detect possible variations in the mitochondrial DNA (mtDNA).Results No deletions but a high frequency of point mutations were found in RPL females; among 129 variations observed in RPL, 22 mutations were significant (P<0.05) and the insertion of C in nucleotide 114 was novel. Conclusion High rate of mutations in D-loop of mtDNA was observed in maternal blood, a fact that may have a direct or indirect role in inducing RPL. The results can be used in the assessment of RPL and designing possible treatments for improving assisted reproduction.

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Section: Discussionmentioning

confidence: 93%

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

Seyedhassani

Houshmand

Kalantar

et al. 2010

J Assist Reprod Genet

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“…23 Moreover, it is ascertained that cancer cells may easily withstand otherwise infrequent pathogenic mutations that affect the respiratory chain, as oxidative metabolism is often shut off in tumors in favor of the Warburg effect. 7,24 It is therefore reasonable to assume that two independent tumors arising in a single individual may not acquire the same somatic mitochondrial DNA genotype, especially as no 'field effects' are known nowadays. This assumption was the basis of our work, as the occurrence of the same, truly somatic (ie, cancer-specific) mutation detected in both endometrial and ovarian cancer, ought to be an unequivocal marker of a common, clonal origin of both cancers, most likely one being a metastasis of the other.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 We recently proposed mitochondrial DNA genotyping as a tool to help identify metastatic ovarian/endometrial cancers. 6 In fact, mitochondrial DNA mutations are extremely common somatic events in human cancers, 7 as the mitochondrial genome is more susceptible to mutations occurrence than nuclear DNA, and they have been shown to help define progression of the disease, such as in the case of endometrial carcinoma. 8 Detection of a random somatic mitochondrial DNA mutation in both endometrial and ovarian cancers of the same patient may be considered as a marker of clonality of the two lesions, as it is virtually impossible that the same tumor-specific mutation may arise in two independent neoplasms.…”

mentioning

confidence: 99%

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

et al. 2014

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Simultaneous independent primary tumors of the female genital tract occur in 1-2% of gynecological cancer patients, 50-70% of which are synchronous tumors of the endometrium and ovary. Recognition of synchrony upon multiple tumors is crucial for correct prognosis, therapeutic choice, and patient management. Current guidelines for determining synchrony, based on surgical and histopathological findings, are often ambiguous and may require further molecular analyses. However, because of the uniqueness of each tumor and of its intrinsic heterogeneity, these analyses may sometimes be inconclusive. A role for mitochondrial DNA genotyping was previously demonstrated in the diagnosis of synchronous endometrial and ovarian carcinoma. We have analyzed 11 sample pairs of simultaneously revealed endometrial and ovarian cancers and have thereby applied conventional histopathological criteria, current molecular analyses (microsatellite instability, b-catenin immunohistochemical staining/CTNNB1 mutation screening), and mitochondrial DNA sequencing to distinguish separate independent tumors from metastases, comparing the performance and the informative potential of such methods. We have demonstrated that in ambiguous interpretations where histopathological criteria and canonical molecular methods fail to be conclusive, mitochondrial DNA analysis may act as a needle of balance and allow to formulate a diagnosis in 45.5% of our cases. Additional advantages of mitochondrial DNA genotyping, besides the high level of information we demonstrated here, are the easy implementation and the need for small amounts of starting material. Our results show that mitochondrial DNA genotyping may provide a substantial contribution to indisputably recognize the metastatic nature of simultaneously detected endometrial and ovarian cancers and may change the final staging and clinical management of these patients. Modern Pathology (2014) 27, 1412-1420; doi:10.1038/modpathol.2014.39; published online 14 March 2014 Keywords: gynecological cancer; mitochondrial DNA mutations; synchronous tumors About 1-2% of women with gynecological cancers are found to have simultaneous independent primary malignancies. Synchronous tumors in the ovary and endometrium are the commonest combination (50-70%) among all synchronous female genital tract malignancies. Only a subset of these can be accurately categorized by standard histological examination. Criteria for synchrony diagnosis were first documented in 1985 1 and subsequently detailed in 1998. 2 Unfortunately, a relevant fraction of cases remains which may not be classified with confidence, either because of widespread involvement, in which case the distinction is of academic rather than practical or prognostic significance, or, more importantly, because of overlapping or

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“…In this report we found that suppression of PNC1 in transformed cells leads to acquisition of a more aggressive phenotype because of an ROS-dependent EMT programme. Mitochondria, and specifically, mutations in mtDNA, have previously been implicated in cancer progression (reviewed in Brandon et al, 2006;Chatterjee et al, 2006). Transfer of mutated mtDNA from highly metastatic cell lines is sufficient to initiate a metastatic phenotype in non-metastatic cell lines by promoting mitochondrial ROS production (Ishikawa et al, 2008).…”

Section: Pnc1 Regulates Mitochondrial Function and Emtmentioning

confidence: 99%

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

et al. 2010

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The insulin-like growth factor (IGF-I) signalling pathway is essential for metabolism, cell growth and survival. It induces expression of the mitochondrial pyrimidine nucleotide carrier 1 (PNC1) in transformed cells, but the consequences of this for cell phenotype are unknown. Here we show that PNC1 is necessary to maintain mitochondrial function by controlling mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. PNC1 suppression causes reduced oxidative phosphorylation and leakage of reactive oxygen species (ROS), which activates the AMPK-PGC1a signalling pathway and promotes mitochondrial biogenesis. Overexpression of PNC1 suppresses mitochondrial biogenesis. Suppression of PNC1 causes a profound ROS-dependent epithelialmesenchymal transition (EMT), whereas overexpression of PNC1 suppresses both basal EMT and induction of EMT by TGF-b. Overall, our findings indicate that PNC1 is essential for mitochondria maintenance and suggest that its induction by IGF-I facilitates cell growth whereas protecting cells from an ROS-promoted differentiation programme that arises from mitochondrial dysfunction.

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Mitochondrial mutations in cancer

Cited by 730 publications

References 84 publications

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

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