HmtDB, a genomic resource for mitochondrion-based human variability studies

Rubino, Francesco; Piredda, Roberta; Calabrese, Francesco Maria; Simone, Domenico; Lang, Martin; Calabrese, Claudia; Petruzzella, Vittoria; Tommaseo-Ponzetta, Mila; Gasparre, Giuseppe; Attimonelli, Marcella

doi:10.1093/nar/gkr1086

Cited by 83 publications

(104 citation statements)

References 33 publications

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“…The current variability estimates for mitochondrial genome positions show that a great part of over 16 500 nucleotides by which the human mitochondrial DNA is composed varies among individuals with different frequency, as it is reported in human mitochondrial databases. 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.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…All variant nucleotide positions and related loci as well as their corresponding codon positions, possible amino acid changes, stop-gains and stop-losses in protein-coding genes were reported in the final annotation file. The process to prioritize the most important candidate variants was mainly based on the recognition of alleles that were not shared with MHCS and sorted by increasing nucleotide variability calculated on multi-aligned complete mitochondrial genomes from 14 144 healthy individuals annotated in Human Mitochondrial DataBase (Rubino et al, 2012). Output values ranged from 0 to 1, where low variability values suggest a private variant.…”

Section: Mapping and Pathogenicity Evaluationmentioning

confidence: 99%

Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis

Vicario

Lang

et al. 2017

Human Reproduction

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STUDY QUESTION: Does selection for mtDNA mutations occur in human oocytes?SUMMARY ANSWER: We provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs).WHAT IS KNOWN ALREADY: Several lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature.STUDY DESIGN, SIZE, DURATION: In this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age.PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO).MAIN RESULTS AND THE ROLE OF CHANCE: Unlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB. LIMITATIONS, REASONS FOR CAUTION:The sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased.

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“…Different web resources, such as Phylotree [1] and MITOMAP [2] besides GenBank and Pubmed, have allowed a variability analysis that has been carried out on mitochondrion genomes of healthy and pathologic individuals within HmtDB [3] where an evaluation of site-specific nucleotide and aminoacid variability is implemented, SiteVar [4]. Pathogenicity analysis has been possible by applying i. Polyphen2 [5] which compares wild type and variant alleles based on the aminoacidic conservation observed in proteins multialignment, and ii.…”

Section: Methodsmentioning

confidence: 99%

Towards an integrated resource for the study of population and disease associated variability of the human mitochondrial genome

Diroma

Attimonelli

2012

EMBnet j.

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MotivationsThanks to the development of valid DNA sequencing technologies and statistical methods of analysis, nowadays we have a great amount of human mtDNA data. The mitochondrion genome presents a high rate of variability: the turning point of a polymorphism into a mutation is linked to heteroplasmy. A variability analysis of sequenced human mtDNAs has been performed by comparing published sequences with the reference sequence, rCRS, to detect and to characterize polymorphic positions in order to recognize relationships between i. variability values and haplogroups patterns, and ii. variability and pathogenicity.

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HmtDB, a genomic resource for mitochondrion-based human variability studies

Cited by 83 publications

References 33 publications

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

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

Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis

Towards an integrated resource for the study of population and disease associated variability of the human mitochondrial genome

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