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Detection of mtMSI in endometrial carcinomas by DNA sequencing. (A) The normal sequence (commencing at np 514, arrows) of U111 (Table 1) is a microsatellite DNA containing four CA repeats. In the tumour, it was expanded to carry five CA repeats. (B) The mtDNA sequence found in the normal tissue of U109 (Table 1) contained heteroplasmic stretch of C residues, comprising C8, C9, C10 and C11 (commencing at np 303, arrows). In the tumour, mtDNA sequence contained mainly C8 and a small proportion of C9.
Source publication
To investigate the occurrence of somatic mitochondrial DNA (mtDNA) mutations in human primary endometrial carcinomas, we sequenced the D-loop region, the 12S and 16S rRNA genes of mtDNA of cancer tissues and their matched normal controls. About 56% (28 out of 50) of cases carry one or more somatic changes in mtDNA including deletion, point mutation...
Citations
... In addition, the D-loop of mtDNA contained multiple point mutations, microsatellite instability alterations, and significant deletions. These modifications may influence mtDNA replication and the transcription of mitochondrial genes [17]. The mitochondrial genome encodes thirteen essential subunits of the oxidative phosphorylation (OXPHOS) machinery in the inner mitochondrial membrane [14]. ...
Estrogens enhance cellular mitochondrial activity. The diminution of female hormones during menopause may have an effect on the mitochondrial genome and the expression of mitochondrial proteins. Hence, oxidative stress and the pro-inflammatory state contribute to the formation of systemic illnesses including arterial hypertension (AH). This study aimed to determine the types and frequency of mutations in the mitochondrial DNA (mtDNA) nucleotide sequence in the hypervariable regions 1 and 2 (HV1 and HV2) and the 12S RNA coding sequence of the D-loop in postmenopausal women with hypertension. In our study, 100 women were investigated, 53 of whom were postmenopausal and 47 of whom were premenopausal (53.9 ± 3.7 years vs. 47.7 ± 4.2 years, respectively). Of those studied, 35 premenopausal and 40 postmenopausal women were diagnosed with AH. A medical checkup with 24 h monitoring of blood pressure (RR) and heart rate was undertaken (HR). The polymorphism of the D-loop and 12S rDNA region of mtDNA was examined. Changes in the nucleotide sequence of mtDNA were observed in 23% of the group of 100 women. The changes were identified in 91.3% of HV1 and HV2 regions, 60.9% of HV1 segments, 47.5% of HV2 regions, and 43.5% of 12S rDNA regions. The frequency of nucleotide sequence alterations in mtDNA was substantially higher in postmenopausal women (34%) than in premenopausal women (10.6%), p = 0.016. A higher frequency of changes in HV1 + HV2 sections in postmenopausal women (30.2%) compared to the premenopausal group (10.6%) was detected, p = 0.011. Only postmenopausal women were found to have modifications to the HV2 segment and the 12S rDNA region. After menopause, polymorphism in the mtDNA region was substantially more frequent in women with arterial hypertension than before menopause (p = 0.030; 37.5% vs. 11.5%). Comparable findings were observed in the HV2 and HV1 regions of the AH group (35% vs. 11.5%), p = 0.015, in the HV1 segment (25% vs. 11.5%), p = 0.529, and in the HV2 segment, 12S rDNA (25% vs. 0%). More than 80% of all changes in nucleotide sequence were homoplasmic. The mtDNA polymorphisms of the nucleotide sequence in the HV1 and HV2 regions, the HV2 region alone, and the 12S RNA coding sequence were associated with estrogen deficiency and a more severe course of arterial hypertension, accompanied by symptoms of adrenergic stimulation.
... Consequently, heteroplasmic mitochondrial populations may consistently amplify even lowfrequency mutations or deletion events. Likewise, mtDNA mutations have been well-described as biomarkers for a variety of malignancies, including those of the bone, brain, breast, lung, colorectal, gastric, ovarian, prostate, and endometrial tissues [185][186][187][188][189][190][191][192][193][194]. Specifically, numerous independent examinations of endometrial malignancies showed mtDNA changes in the endometrium [195][196][197]. ...
Endometriosis, a benign gynecologic and chronic inflammatory disease, is defined by the presence of endometrial tissue outside the uterus characterized mainly by pelvic pain and infertility. Because endometriosis affects approximately 10% of females, it represents a significant socioeconomic burden worldwide having tremendous impact on daily quality of life. Accurate and prompt diagnosis is crucial for the management of this debilitating disorder. Unfortunately, diagnosis is typically delayed to lack of specific symptoms and readily accessible biomarkers. Although histopathologic examination remains the current gold standard, this approach is highly invasive and not applicable for early screening. Recent work has focused on the identification of reliable biomarkers including immunologic, ie, immune cells, antibodies and cytokines, as well as genetic and biochemical markers, ie, microRNAs, lncRNAs, circulating and mitochondrial nucleic acids, along with some hormones, glycoproteins and signaling molecules. Confirmatory research studies are, however, needed to more fully establish these markers in the diagnosis, progression and staging of these endometrial lesions.
... The poly-C repeat located between 303 and 315 nucleotides and interrupted by a T base at position 310 (termed as D310) has been recognized as a frequent hotspot of deletion/insertion mutations in various multifactorial diseases and cancers [73][74][75][76][77][78]. D310 alterations were initially discovered in 2001 by Sanchez-Cespedes et al. in several types of tumours [75]. ...
... The mtMSI was first described in ovarian cancer samples (20%, 3/15) by Liu et al. in 2001 [91]. Two years later, a follow-up study of mtMSI was conducted by the authors on 50 samples of primary endometrial carcinomas, revealing a higher rate of mtMSI (50%), particularly detected in 3 different regions (D310, D514, and D16184) of the D-loop region and one in the 12S RNA gene [73]. ...
Cancer has been broadly considered a genetic disease involving mutations in nuclear DNA and the mitochondrial genome (mtDNA). Mitochondria are essential bioenergetics and biosynthetic machinery found in most eukaryotic organisms. Thus, failure of their function is crucial for tumourigenesis, tumour cell growth, and metastasis. Mitochondrial dysregulation can occur as a consequence of molecular alterations in mtDNA, such as point mutations, deletions, inversions, microsatellite instability (MSI), and copy number variations. This review article aims to highlight the published research work on alterations in mtDNA, with a particular focus on mitochondrial MSI (mtMSI) in various types of solid cancers. Databases including PubMed, Scopus, and Google Scholar were searched for articles about mtMSI and its link to solid cancer published from 1990 till 2021. In this review, we briefly summarize the knowledge related to possible molecular mechanisms causing mtMSI formation and the available information on mtMSI frequency values in all main solid cancer types. Mutations in the mitochondrial genome are widely believed to have a broad impact across various cancers. Based on the available published data, mtMSI can act as a vital risk factor and a potential marker for cancer progression. Further research is required to unravel the role of mtMSI in tumourigenesis.
... Curiously, no studies were found reporting a positive association with such variants in cancer, except for 16189 (D-loop). This mutation, which is suggested to generate mitochondrial impairment and genome instability, has been related to different complex conditions, such as endometriosis [17], coronary artery disease [18], type 2 diabetes mellitus and metabolic syndrome [19], as well as multiple types of cancer, namely, endometrial [20], breast [21], colorectal [22] and acute myeloid leukaemia [23]. ...
Background
Mitochondrial participation in tumorigenesis and metastasis has been studied for many years, but several aspects of this mechanism remain unclear, such as the association of mitochondrial DNA (mtDNA) with different cancers. Here, based on two independent datasets, we modelled an mtDNA mutation-cancer network by systematic integrative analysis including 37 cancer types to identify the mitochondrial variants found in common among them.
Results
Our network showed mtDNA associations between gastric cancer and other cancer types, particularly kidney, liver, and prostate cancers, which is suggestive of a potential role of such variants in the metastatic processes among these cancer types. A graph-based interactive web tool was made available at www2.lghm.ufpa.br/mtdna. We also highlighted that most shared variants were in the MT-ND4 , MT-ND5 and D-loop, and that some of these variants were nonsynonymous, indicating a special importance of these variants and regions regarding cancer progression, involving genomic and epigenomic alterations.
Conclusions
This study reinforces the importance of studying mtDNA in cancer and offers new perspectives on the potential involvement of different mitochondrial variants in cancer development and metastasis.
... Another potential marker and a common mtMSI is D16184, with a similar wild-type structure to D310 (homopolymeric C stretch with T nucleotide interruption) [174]. The D16184 was located in the hypervariable region I (HVRI), in proximity to the 3′-end of terminationassociated sequence within the 7S DNA binding site, thus vital for mtDNA biogenesis [182]. A vast number of studies reported the presence of D16184 involving various cancer types such as gastric (16.1%) [183] and endometrial 9 Disease Markers carcinoma (14%) [182], interestingly at high prevalence (70.3%) in a recent acute myeloid leukemia study [184]. ...
... The D16184 was located in the hypervariable region I (HVRI), in proximity to the 3′-end of terminationassociated sequence within the 7S DNA binding site, thus vital for mtDNA biogenesis [182]. A vast number of studies reported the presence of D16184 involving various cancer types such as gastric (16.1%) [183] and endometrial 9 Disease Markers carcinoma (14%) [182], interestingly at high prevalence (70.3%) in a recent acute myeloid leukemia study [184]. ...
Cancer is a heterogeneous group of diseases, the progression of which demands an accumulation of genetic mutations and epigenetic alterations of the human nuclear genome or possibly in the mitochondrial genome as well. Despite modern diagnostic and therapeutic approaches to battle cancer, there are still serious concerns about the increase in death from cancer globally. Recently, a growing number of researchers have extensively focused on the burgeoning area of biomarkers development research, especially in noninvasive early cancer detection. Intergenomic cross talk has triggered researchers to expand their studies from nuclear genome-based cancer researches, shifting into the mitochondria-mediated associations with carcinogenesis. Thus, it leads to the discoveries of established and potential mitochondrial biomarkers with high specificity and sensitivity. The research field of mitochondrial DNA (mtDNA) biomarkers has the great potential to confer vast benefits for cancer therapeutics and patients in the future. This review seeks to summarize the comprehensive insights of nuclear genome cancer biomarkers and their usage in clinical practices, the intergenomic cross talk researches that linked mitochondrial dysfunction to carcinogenesis, and the current progress of mitochondrial cancer biomarker studies and development.
... Insertions and deletions (indels) in the poly C stretch of the D-loop region were mostly present in this study. mtMSI (specifically in the D310 area) has now been targeted in several cancers (3,8,30,38,41,60,63,69) since this region was first recognized 19 years ago by Sanchez-Cespedes et al. as a mutational hotspot (55). The D310 is a highly polymorphic region, located within the hypervariable II (HV II) region. ...
... The instability in the nucleotide positions 16184-16193 is another remarkable mutational hotspot in the mitochondrial D-loop and has been extensively studied in several cancers (3,8,10,17,28,30,39,41). The 16184-16193 region is an unstable tract of poly cytosine residues and is prone to replication errors, most likely due to polymerase slippage. ...
... A recent finding of Kim et al. showed a strikingly high frequency of mtMSI at D16184 in acute myeloid leukemia among Korean patients (70.3%) (25). As observed in another study, the presence of poly C stretch alterations in D16184 locus has also been detected among gastric carcinoma (16.1%) (17), and endometrial carcinoma patients (14.0%) (41). ...
Aim:
To determine the mitochondrial microsatellite instability (mtMSI) status in a series of Malaysian patients with brain tumors. Furthermore, we analyzed whether the mtMSI status is associated with the clinicopathological features of the patients.
Material and methods:
Forty fresh frozen tumor tissues along with blood samples of brain tumor patients were analyzed for mtMSI by PCR amplification of genomic DNAs, and the amplicons were directly sequenced in both directions using Sanger sequencing.
Results:
Microsatellite analysis revealed that 20% (8 out of 40) of the tumors were mtMSI positive with a total of 8 mtMSI changes. All mtMSI markers were detected in D310 and D16184 of the D-loop region. Additionally, no significant association was observed between mtMSI status and clinicopathological features.
Conclusion:
The variations, specifically the mtMSI, suggest that the mitochondrial DNA (mtDNA) can be targeted for genomic alteration in brain tumors. Therefore, the specific role of mtDNA alteration in brain tumor development and prognosis requires further investigation.
... Some 56% (28 of 50) of frozen samples of primary endometrial carcinoma obtained from surgery carried one or more somatic mtDNA mutations, only occurring in the tumor. The D-loop was most frequently affected, and the predominant type of mutation were mitochondrial microsatellite instabilities (mtMSI) [71]. In the 12S rRNA gene either novel mtMSI were found carrying a deletion or insertion of one cytosine residue in front of the thymine or a germline T to C polymorphism was discovered, producing a homopolymorphic C tract resulting in a DNA instability [71]. ...
... The D-loop was most frequently affected, and the predominant type of mutation were mitochondrial microsatellite instabilities (mtMSI) [71]. In the 12S rRNA gene either novel mtMSI were found carrying a deletion or insertion of one cytosine residue in front of the thymine or a germline T to C polymorphism was discovered, producing a homopolymorphic C tract resulting in a DNA instability [71]. The base substitution 16189T to C from np 16,024 to 576 have many cancers in common including endometrial, cervical and ovary cancer [72]. ...
... The base substitution 16189T to C from np 16,024 to 576 have many cancers in common including endometrial, cervical and ovary cancer [72]. Some 32% (16 out of 50) of samples showed changes in the length of a homopolymorphic cytosine at np 303-309 [71]. Within the 7S DNA binding site at the 3′ end and the termination-associated sequence, a CCCCCTCCCC mtMSI was found, leading to an uninterrupted C tract unstable in the tumor [71]. ...
Endometrial cancer (EC) is a common gynecologic malignancy which continues to have a poor prognosis in advanced stages due to current therapeutic limitations. A significant mechanism of chemoresistance in EC has been shown to also be the enhancement of epithelial to mesenchymal transition (EMT) and the subsequent obtainment of stem cell-like characteristics of EC. Current evidence on EMT in EC however fails to explain the relationship leading to an EMT signaling enhancement. Our review therefore focuses on understanding eukaryotic translation initiation factors (eIFs) as key regulators of the translational process in enhancing EMT and subsequently impacting higher chemoresistance of EC. We identified pathways connected to the development of a microenvironment for EMT, inducers of the process specifically related to estrogen receptors as well as their interplay with eIFs. In the future, investigation elucidating the translational biology of EC in EMT may therefore focus on the signaling between protein kinase RNA-like ER kinase (PERK) and eIF2alpha as well as eIF3B.
... High rate substitution frequency in mitochondrial genome which have been associated with increased cancer risk suggesting that mtDNA mutations might be significant in the etiology of certain cancers [19,20] such as bladder, head and neck, and lung cancers [21], gastric tumors [22], hepatocellular carcinomas [23,24], glioblastomas [25], thyroid tumors [26], papillary thyroid carcinomas [27], Ovarian tumors [28], breast cancer samples [29] and prostate cancer tumors [30][31][32]. One of the first evidence based on the role of the mitochondrial genome in cancer progression was the study of ND3 gene mutations that were linked to increased risk for invasive breast and endometrial cancers in African-American women [33,34]. Further evidence for the role of mtDNA variants in cancer risk came from a study of mtDNA COX1 gene mutations in European-American prostate cancer cases. ...
Background:
Familial adenomatous polyposis (FAP) is an Autosomal dominant inherited disorder and a rare form of colorectal cancer (CRC) that is characterized by the development of hundreds to thousands of adenomas in the rectum and colon. Mostly, cancers develop after the advent of the polyps. It appears in both sexes evenly, and the occurrence of the disease is in the second decade of life. Mitochondrial genome mutations have been reported with a variety of Tumors, but the precise role of these mutations in the pathogenicity and tumor progression is not exactly clear. Cytochrome c oxidase subunit I (COX1) is the terminal enzyme of the mitochondrial respiratory chain. The present study aims at assessing the occurrence of mtDNA mutations in COX1 gene in FAP patients and attempts to find out the cause and effect relationship between mitochondrial mutations and tumor progression.
Methods:
In this study, 56 FAP patients were investigated for the presence of the mutations in mitochondrial COX1 coding gene by PCR and sequencing analysis. All sequences that differed from the revised Cambridge Reference Sequence (rCRS) were classified as missense/ nonsense or silent mutations. Functional genomic studies using Bio-informatics tools were performed on the founded mutations to understand the downstream alterations in structure and function of protein.
Results:
We identified 38 changes in the COX1 gene in patients with FAP symptoms. Most of them were heteroplasmic changes of missense type (25/38). Tree of the changes (G6145A, C6988A, and T7306G) were nonsense mutations and had not been reported in the literature before. Our results of bioinformatics predictions showed that the identified mutations can affect mitochondrial functions, especially if the conservative domain of the protein is concerned.
Conclusion:
Our findings indicate a high frequency of mtDNA mutations in all of the FAP cases compared to matched controls. These data significantly enhance our understanding of how such mutations contribute to cancer pathologies and develop the cancer treatment methods by new diagnostic biomarkers, and new drugs for gene therapy.
... As a result, even lowfrequency mutations or deletion events can be amplified reliably from heteroplasmic mitochondrial populations. Indeed, mtDNA mutations have been well-described as biomarkers for several cancers across multiple body sites including bone, brain, breast, lung, colorectal, gastric, ovarian, prostate and endometrial tissues [28][29][30][31][32][33][34][35][36][37]. Specifically, within the endometrium, mtDNA alterations were detected during multiple independent investigations of endometrial cancers [37][38][39][40]. ...
... Indeed, mtDNA mutations have been well-described as biomarkers for several cancers across multiple body sites including bone, brain, breast, lung, colorectal, gastric, ovarian, prostate and endometrial tissues [28][29][30][31][32][33][34][35][36][37]. Specifically, within the endometrium, mtDNA alterations were detected during multiple independent investigations of endometrial cancers [37][38][39][40]. Although those studies did not reveal a consensus region within the mtDNA genome or a specific mtDNA alteration that correlated to endometrial disease, those data do support the tenet that changes in mtDNA could be used as a biomarker for detection of endometriosis. ...
Aim:
Accurate noninvasive diagnostic aids for endometriosis are needed. We evaluated mitochondrial DNA deletions as potential biomarkers for endometriosis.
Methods:
The diagnostic accuracy of deletions was evaluated by quantitative polymerase chain reaction (QPCR) using well-characterized clinical specimens from all subtypes and stages of endometriosis in a case-control format (n = 182).
Results:
Deletions (1.2 and 3.7 kb) detected in blood differentiated between endometriosis and controls (area under the curve [AUC] 0.71-0.90). Differences in deletion levels were statistically significant (p < 0.05) for all disease subtypes and stages. Neither deletion was correlated with patient or specimen age or hormone status. The 1.2 kb deletion was not correlated with menstrual stage; the 3.7 kb deletion was significantly correlated between two of the groups.
Conclusion:
Biomarkers of the mitochondrial genome, including the deletions described here, offer a promising and largely unexplored avenue in the pursuit of diagnostic markers for endometriosis that can be effectively translated to clinical application.
... • mtDNA mutations reported in esophageal, endometrial [181,182], colorectal [183], prostate [221], breast [222], ovarian [223], gastric [224], hepatocellular [225], pancreatic [226] and lung cancers [227] as well as several others (reviewed in [228] tissue increases with age and plays a role in age-related increases in heart disease prevalence. Conversely, there is a reasonable level of evidence supporting an important role for mtDNA in heart function as many mtDNA mutations result in changes to cardiac function (reviewed in [162]). ...
... As a consequence of this, many studies have searched for evidence of mitochondrial genome instability in cancer. Esophageal and endometrial carcinomas have indeed been associated with the appearance of mtDNA point mutations, especially in the D-Loop region [181,182]. Strikingly, in a study of human colorectal cancer, it was reported that tumor tissue had a lower random mutation frequency than non-neoplasic tissue [183]. The authors argued that mtDNA genome stability in such tumors may have risen due to lower ROS production and therefore less oxidative damage. ...
The mitochondrial genome (mtDNA) represents a tiny fraction of the whole genome, comprising just 16.6 kilobases encoding 37 genes involved in oxidative phosphorylation and the mitochondrial translation machinery. Despite its small size, much interest has developed in recent years regarding the role of mtDNA as a determinant of both aging and age-associated diseases. A number of studies have presented compelling evidence for key roles of mtDNA in age-related pathology, although many are correlative rather than demonstrating cause. In this review we will evaluate the evidence supporting and opposing a role for mtDNA in age-associated functional declines and diseases. We provide an overview of mtDNA biology, damage and repair as well as the influence of mitochondrial haplogroups, epigenetics and maternal inheritance in aging and longevity.
