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Aggarwal P, Gunasekaran V, Sood A, Mittal BR. Localization in primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab 2025; 39:101967. [PMID: 39755470 DOI: 10.1016/j.beem.2024.101967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Primary hyperparathyroidism is the main cause of hypercalcemia, resulting predominantly from parathyroid adenomas followed by hyperplasia. Diagnosis relies on clinical and biochemical parameters. Accurate pre-operative localization is mandatory for better surgical outcome. Various non-invasive imaging modalities includes cervical ultrasound, radionuclide scintigraphy with 99mTc-Methoxyisobutyl isonitrile combined with SPECT/CT, 4DCT, MRI and 18F-Choline PET/CT. Functional imaging has shown higher accuracy in localization especially in ectopic parathyroid adenomas and persistent or recurrent hyperparathyroidism. Combined ultrasound and 99mTc-MIBI has shown high sensitivity and specificity than individual imaging modality. 18F-Choline PET/CT has better diagnostic performance in identifying parathyroid hyperplasia and multiple adenomas. In patients with equivocal findings and concurrent thyroid nodular diseases, 18F-Choline PET/MRI and 4DCT helps in better characterization of lesion. Intraoperative probe guided surgery facilitates targeted and minimally invasive surgery resulting in better surgical outcome. More specific radiopharmaceuticals for parathyroid imaging need to be developed to reduce false positive results.
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Affiliation(s)
- Piyush Aggarwal
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India.
| | - Vinisha Gunasekaran
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India.
| | - Ashwani Sood
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India.
| | - Bhagwant Rai Mittal
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India.
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Geng C, Liu J, Guo B, Liu K, Gong P, Wang B, Wan Q, Sun L, Zhao J, Song Y. High lymphocyte signature genes expression in parathyroid endocrine cells and its downregulation linked to tumorigenesis. EBioMedicine 2024; 102:105053. [PMID: 38471398 PMCID: PMC10945207 DOI: 10.1016/j.ebiom.2024.105053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND To date, because of the difficulty in obtaining normal parathyroid gland samples in human or in animal models, our understanding of this last-discovered organ remains limited. METHODS In the present study, we performed a single-cell transcriptome analysis of six normal parathyroid and eight parathyroid adenoma samples using 10 × Genomics platform. FINDINGS We have provided a detailed expression atlas of parathyroid endocrine cells. Interestingly, we found an exceptional high expression levels of CD4 and CD226 in parathyroid endocrine cells, which were even higher than those in lymphocytes. This unusual expression of lymphocyte markers in parathyroid endocrine cells was associated with the depletion of CD4 T cells in normal parathyroid glands. Moreover, CD4 and CD226 expression in endocrine cells was significantly decreased in parathyroid adenomas, which was associated with a significant increase in Treg counts. Finally, along the developmental trajectory, we discovered the loss of POMC, ART5, and CES1 expression as the earliest signature of parathyroid hyperplasia. INTERPRETATION We propose that the loss of CD4 and CD226 expression in parathyroid endocrine cells, coupled with an elevated number of Treg cells, could be linked to the pathogenesis of parathyroid adenoma. Our data also offer valuable information for understanding the noncanonical function of CD4 molecule. FUNDING This work was supported by the National Key R&D Program of China (2022YFA0806100), National Natural Science Foundation of China (82130025, 82270922, 31970636, 32211530422), Shandong Provincial Natural Science Foundation of China (ZR2020ZD14), Innovation Team of Jinan (2021GXRC048) and the Outstanding University Driven by Talents Program and Academic Promotion Program of Shandong First Medical University (2019LJ007).
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Affiliation(s)
- Chong Geng
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324 Jingwu Road, Jinan, Shandong 250021, China
| | - Junjun Liu
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Jinan, Shandong 250013, China; Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University, No.324 Jingwu Road, Jinan, Shandong 250021, China
| | - Bingzhou Guo
- College of Artificial Intelligence and Big Data for Medical Sciences, Shandong First Medical University, No.6699 Qingdao Road Jinan, Shandong 250021, China
| | - Kailin Liu
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324 Jingwu Road, Jinan, Shandong 250021, China
| | - Pengfei Gong
- College of Artificial Intelligence and Big Data for Medical Sciences, Shandong First Medical University, No.6699 Qingdao Road Jinan, Shandong 250021, China
| | - Bao Wang
- Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University, No.324 Jingwu Road, Jinan, Shandong 250021, China
| | - Qiang Wan
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Jinan, Shandong 250013, China.
| | - Liang Sun
- College of Artificial Intelligence and Big Data for Medical Sciences, Shandong First Medical University, No.6699 Qingdao Road Jinan, Shandong 250021, China.
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324 Jingwu Road, Jinan, Shandong 250021, China; Shandong Clinical Research Center of Diabetes and Metabolic Diseases, No.324 Jingwu Road, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University, No.324 Jingwu Road, Jinan, Shandong 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, No.324 Jingwu Road, Jinan, Shandong 250021, China.
| | - Yongfeng Song
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Jinan, Shandong 250013, China; Shandong Clinical Research Center of Diabetes and Metabolic Diseases, No.324 Jingwu Road, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University, No.324 Jingwu Road, Jinan, Shandong 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, No.324 Jingwu Road, Jinan, Shandong 250021, China.
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Romero-Velez G, Noureldine SI, Rahman M, Bena JF, Burneikis T, Jin J. Are 99mTC-Sestamibi Single Photon Emission Computed Tomography Scan Results Associated to the Parathyroid Cell Type in Primary Hyperparathyroidism? J Surg Res 2024; 293:517-524. [PMID: 37827030 DOI: 10.1016/j.jss.2023.08.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 07/28/2023] [Accepted: 08/27/2023] [Indexed: 10/14/2023]
Abstract
INTRODUCTION 99mTC-sestamibi scintigraphy (SPECT-CT) is a common imaging modality for parathyroid localization in primary hyperparathyroidism (PHPT). Prior studies have suggested that the cellular composition of parathyroid adenomas influences SPECT-CT imaging results. Other biochemical and anatomical factors may also play a role in false negative results. Therefore, after controlling for confounding variables, we sought to determine whether the histologic composition of parathyroid adenomas is associated to SPECT-CT results in patients with single gland disease causing PHPT. METHODS A retrospective review of patients with PHPT due to confirmed single gland disease was performed over a 2-y period. A 1:1 propensity score matching was done between patients with positive and negative SPECT-CT results with regard to demographical, biochemical, and anatomical characteristics followed by blinded pathologic examination of cell composition in the matched pairs. RESULTS Five hundred forty two patients underwent routine four gland exploration and 287 (53%) patients were found to have a single adenoma. Of those, 26% had a negative SPECT-CT result. There were significant differences between groups with regards to biochemical profile, gland location, and gland size. All of which became nonsignificant after propensity score matching. Adenomas were primarily composed of chief cells, with no difference between groups (95% versus 97%, P = 0.30). In the positive SPECT-CT group, chief cells were the dominant cell type in 68% of the cases, followed by mixed type (13%), oxyphil cells (12%), and clear cells (7%). This was similar to the negative SPECT-CT group (P = 0.22). CONCLUSIONS While certain patient's clinical characteristics are associated with SPECT-CT imaging results, histologic cell type is not significantly associated.
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Affiliation(s)
- Gustavo Romero-Velez
- Endocrinology and Metabolism Institute, Department of Endocrine Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Salem I Noureldine
- Department of Surgery, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Mobeen Rahman
- Pathology and Laboratory Medicine Institute, Department of Pathology, Cleveland Clinic, Cleveland, Ohio
| | - James F Bena
- Lerner Research Institute, Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
| | - Talia Burneikis
- Department of Endocrine and General Surgery, Integris Baptist Medical Center, Oklahoma City, Oklahoma
| | - Judy Jin
- Endocrinology and Metabolism Institute, Department of Endocrine Surgery, Cleveland Clinic, Cleveland, Ohio.
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Tu CL, Chang W, Sosa JA, Koh J. Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency. PNAS NEXUS 2023; 2:pgad073. [PMID: 36992820 PMCID: PMC10042281 DOI: 10.1093/pnasnexus/pgad073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/22/2023] [Accepted: 03/02/2023] [Indexed: 03/12/2023]
Abstract
Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder characterized by disrupted calcium homeostasis secondary to inappropriately elevated parathyroid hormone (PTH) secretion. Low levels of serum 25-hydroxyvitamin D (25OHD) are significantly more prevalent in PHPT patients than in the general population (1-3), but the basis for this association remains unclear. We employed a spatially defined in situ whole-transcriptomics and selective proteomics profiling approach to compare gene expression patterns and cellular composition in parathyroid adenomas from vitamin D-deficient or vitamin D-replete PHPT patients. A cross-sectional panel of eucalcemic cadaveric donor parathyroid glands was examined in parallel as normal tissue controls. Here, we report that parathyroid tumors from vitamin D-deficient PHPT patients (Def-Ts) are intrinsically different from those of vitamin D-replete patients (Rep-Ts) of similar age and preoperative clinical presentation. The parathyroid oxyphil cell content is markedly higher in Def-Ts (47.8%) relative to Rep-Ts (17.8%) and normal donor glands (7.7%). Vitamin D deficiency is associated with increased expression of electron transport chain and oxidative phosphorylation pathway components. Parathyroid oxyphil cells, while morphologically distinct, are comparable to chief cells at the transcriptional level, and vitamin D deficiency affects the transcriptional profiles of both cell types in a similar manner. These data suggest that oxyphil cells are derived from chief cells and imply that their increased abundance may be induced by low vitamin D status. Gene set enrichment analysis reveals that pathways altered in Def-Ts are distinct from Rep-Ts, suggesting alternative tumor etiologies in these groups. Increased oxyphil content may thus be a morphological indicator of tumor-predisposing cellular stress.
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Affiliation(s)
- Chia-Ling Tu
- Endocrine Research Unit, Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94158
| | - Wenhan Chang
- Endocrine Research Unit, Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94158
| | - Julie A Sosa
- Endocrine Neoplasia Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA 94143
| | - James Koh
- Endocrine Neoplasia Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA 94143
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Hönigova K, Navratil J, Peltanova B, Polanska HH, Raudenska M, Masarik M. Metabolic tricks of cancer cells. Biochim Biophys Acta Rev Cancer 2022; 1877:188705. [PMID: 35276232 DOI: 10.1016/j.bbcan.2022.188705] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/11/2022] [Accepted: 02/26/2022] [Indexed: 12/15/2022]
Abstract
One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.
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Affiliation(s)
- Katerina Hönigova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Jiri Navratil
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Barbora Peltanova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Hana Holcova Polanska
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Martina Raudenska
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Michal Masarik
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic.
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Hu Y, Zhang X, Wang O, Xing X, Cui M, Wang M, Song C, Liao Q. Spectrum of mitochondrial genomic variation in parathyroid neoplasms. Endocrine 2021; 74:690-697. [PMID: 34296389 DOI: 10.1007/s12020-021-02825-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/10/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Mitochondrial DNA (mtDNA) variations have been implicated in various cancer types. Several attempts have been made in benign parathyroid adenoma (PA); however, mtDNA variants and copy number alterations have not been investigated in parathyroid carcinoma (PC). The present study aimed to explore the variations in the mitochondrial genome in parathyroid neoplasms. METHODS In this study, ultradeep targeted sequencing of mtDNA was performed in 12 cases with PC and 25 cases with PA. Germline and somatic variants in the mitochondrial genome were analysed according to clinical features. The mtDNA copy number relative to nuclear DNA was measured. RESULTS A total of 821 germline variants and 23 somatic mutations were identified. All 160 germline nonsynonymous variants in the coding sequence (CDS) were predicted to be likely benign, and germline variants frequently occurred (26.3%) in the displacement loop region. Tumour somatic mutation in a CDS with heteroplasmic factor (HF) >0.8 showed a higher mtDNA copy number (p = 0.039). Using Spearman's rank test, tumour mtDNA copy number revealed a positive correlation with serum levels of intact parathyroid hormone and calcium. CONCLUSION Our results demonstrate that null recurrent mtDNA mutational hotspots were PC specific. An increased mtDNA copy number in parathyroid neoplasms was associated with somatic CDS mutations with a high HF and major clinical features. Larger cohort investigations should be performed in future analyses.
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Affiliation(s)
- Ya Hu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiang Zhang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ou Wang
- Department of Endocrinology, Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaoping Xing
- Department of Endocrinology, Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ming Cui
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mengyi Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Chengli Song
- Novogene Bioinformatics Institute, Beijing, China
| | - Quan Liao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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Ferrari C, Santo G, Mammucci P, Pisani AR, Sardaro A, Rubini G. Diagnostic Value of Choline PET in the Preoperative Localization of Hyperfunctioning Parathyroid Gland(s): A Comprehensive Overview. Biomedicines 2021; 9:biomedicines9030231. [PMID: 33669104 PMCID: PMC7996619 DOI: 10.3390/biomedicines9030231] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/13/2021] [Accepted: 02/18/2021] [Indexed: 12/03/2022] Open
Abstract
Hyperparathyroidism is a metabolic disorder characterized by the excessive production of the parathyroid hormone. The diagnosis is based on clinical and laboratory data. In most cases the only treatment is surgery and a correct preoperatory localization of the hyperfunctioning parathyroid gland(s) is essential. Currently, ultrasonography combined with [99mTc]Tc-MIBI parathyroid scintigraphy, optionally associated with single photon emission computed tomography/computed tomography (SPECT/CT), represent the standard preoperative imaging. In recent years, a number of studies have evaluated the potential role of choline positron emission tomography (PET) in hyperparathyroidism with promising results. Most of the recent evidence underlined its higher sensitivity and diagnostic accuracy in the localization of hyperfunctioning parathyroid glands. Choline PET has a higher spatial resolution that is useful for the detection of smaller parathyroid glands and it also has shorter examination times and favorable radiation exposure. These are just a few of the aspects that support it to overcome traditional imaging. Moreover, from the preliminary data, the choline uptake mechanism seems to also have an impact on its better performance. For these reasons, if first used as second level imaging in patients with negative or inconclusive traditional imaging results, several authors have supported its use as a first line investigation. This comprehensive overview aims to provide an accurate description of the preliminary results available in the literature about the use of choline PET/CT in hyperparathyroidism and to compare these results with the performance of traditional imaging methods.
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Affiliation(s)
- Cristina Ferrari
- Nuclear Medicine Unit, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; (C.F.); (G.S.); (P.M.); (A.R.P.); (G.R.)
| | - Giulia Santo
- Nuclear Medicine Unit, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; (C.F.); (G.S.); (P.M.); (A.R.P.); (G.R.)
| | - Paolo Mammucci
- Nuclear Medicine Unit, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; (C.F.); (G.S.); (P.M.); (A.R.P.); (G.R.)
| | - Antonio Rosario Pisani
- Nuclear Medicine Unit, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; (C.F.); (G.S.); (P.M.); (A.R.P.); (G.R.)
| | - Angela Sardaro
- Section of Radiology and Radiation Oncology, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy
- Correspondence:
| | - Giuseppe Rubini
- Nuclear Medicine Unit, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy; (C.F.); (G.S.); (P.M.); (A.R.P.); (G.R.)
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Hu Y, Zhang X, Wang O, Cui M, Li X, Wang M, Hua S, Liao Q. Integrated Whole-Exome and Transcriptome Sequencing of Sporadic Parathyroid Adenoma. Front Endocrinol (Lausanne) 2021; 12:631680. [PMID: 34054720 PMCID: PMC8163014 DOI: 10.3389/fendo.2021.631680] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 03/15/2021] [Indexed: 01/09/2023] Open
Abstract
PURPOSE Hyperparathyroidism is the third most common endocrine disease. Parathyroid adenoma (PA) accounts for approximately 85% of cases of primary hyperparathyroidism, but the molecular mechanism is not fully understood. Herein, we aimed to investigate the genetic and transcriptomic profiles of sporadic PA. METHODS Whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) of 41 patients with PA and RNA-seq of 5 normal parathyroid tissues were performed. Gene mutations and characterized expression changes were identified. To elucidate the molecular mechanism underlying PA, unsupervised consensus clustering of RNA-seq data was performed. The correlations between the sequencing data and clinicopathological features of these patients were analyzed. RESULTS Previously reported PA driver gene mutations, such as MEN1 (9/41), mTOR (4/41), ZFX (3/41), CASR (3/41), EZH2 (2/41) and FAT1 (2/41), were also identified in our cohort. Furthermore, somatic mutation of EZH1, which had not been reported in PA, was found in 4 samples. RNA-seq showed that the expression levels of 84 genes were upregulated and 646 were downregulated in PA samples compared with normal samples. Unsupervised clustering analysis of RNA-seq data clustered these patients into 10 subgroups related to mutation or abnormal expression of a group of potential pathogenic genes. CONCLUSION MEN1, EZH2, CASR, EZH1, ZFX, mTOR and FAT1 mutations in PA were revealed. According to the RNA-seq data clustering analysis, cyclin D1, β-catenin, VDR, CASR and GCM2 may be important factors contributing to the PA gene expression profile.
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Affiliation(s)
- Ya Hu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiang Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ou Wang
- Laboratory of Endocrinology, Department of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ming Cui
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaobin Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mengyi Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Surong Hua
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Quan Liao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- *Correspondence: Quan Liao,
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Suh HY, Na HY, Park SY, Choi JY, So Y, Lee WW. The Usefulness of Maximum Standardized Uptake Value at the Delayed Phase of Tc-99m sestamibi single-photon emission computed tomography/computed tomography for Identification of Parathyroid Adenoma and Hyperplasia. Medicine (Baltimore) 2020; 99:e21176. [PMID: 32664158 PMCID: PMC7360288 DOI: 10.1097/md.0000000000021176] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Tc-99m sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) has been used to help surgeons explore the location of parathyroid diseases, but quantitative parameters have not been systemically investigated for this purpose. We aimed to establish objective criteria for adenoma and hyperplasia using the standardized uptake value (SUV) in patients with hyperparathyroidism.Thirty-nine hyperparathyroid patients (male/female: 17/22, age: 58.33 ± 11.69 years) with at least 1 uptake-positive lesion of any degree by visual assessment in preoperative Tc-99m sestamibi quantitative SPECT/CT were included from Oct 2015 to Oct 2017. Pathologically, 44 lesions (32 adenomas and 12 hyperplasia) were identified. All patients experienced normalized levels of intact parathyroid hormone immediately after surgery. Quantitative SPECT/CT was performed at 10 minute and 2 hour post injection of Tc-99m sestabmibi (dose = 740 MBq), and maximum SUV (SUVmax) was measured for the parathyroid lesions. Experienced pathologists evaluated the percentage cellular proportions of chief cells, oxyphil cells, and clear cells.SUVmax (g/mL) of adenomas, hyperplasia, and reference thyroid tissue were 12.92 ± 6.68, 7.90 ± 5.49, and 7.01 ± 2.62 at 10min (early phase), decreasing to 7.46 ± 5.66, 4.65 ± 3.14, and 2.21 ± 1.07 at 2 hour (delayed phase), respectively. The adenomas showed significantly higher SUVmax than both the hyperplasia (P = .0131) and reference thyroid tissue (P < .0001) along the early and delayed phases, but the SUVmax of the hyperplasia did not differ from that of the reference thyroid tissue (P = .4196). The adenomas and hyperplasia were discriminated from the reference thyroid tissue using a cutoff SUVmax of 3.26 at the delayed phase. The adenomas had lower %proportions of oxyphil cells than the hyperplasia (P = .0054), but its SUVmax at the delayed phase was positively correlated with the %proportions of mitochondria-abundant oxyphil cells (rho = 0.418, P = .0173). The hyperplasia showed no correlation between SUVmax and cellular proportions.SUVmax at the delayed phase in the Tc-99m sestamibi quantitative SPECT/CT was useful for the identification and differentiation of parathyroid lesions causing hyperparathyroidism.
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Affiliation(s)
- Hoon Young Suh
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University
| | | | | | - June Young Choi
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine
| | - Young So
- Department of Nuclear Medicine, Konkuk University Medical Center, Konkuk University School of Medicine
| | - Won Woo Lee
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine
- Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea
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De Luise M, Girolimetti G, Okere B, Porcelli AM, Kurelac I, Gasparre G. Molecular and metabolic features of oncocytomas: Seeking the blueprints of indolent cancers. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2017; 1858:591-601. [DOI: 10.1016/j.bbabio.2017.01.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 12/28/2016] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
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Guerra F, Arbini AA, Moro L. Mitochondria and cancer chemoresistance. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2017; 1858:686-699. [DOI: 10.1016/j.bbabio.2017.01.012] [Citation(s) in RCA: 232] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 01/23/2017] [Accepted: 01/24/2017] [Indexed: 01/07/2023]
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12
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Correia M, Pinheiro P, Batista R, Soares P, Sobrinho-Simões M, Máximo V. Etiopathogenesis of oncocytomas. Semin Cancer Biol 2017; 47:82-94. [PMID: 28687249 DOI: 10.1016/j.semcancer.2017.06.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 06/27/2017] [Accepted: 06/28/2017] [Indexed: 01/01/2023]
Abstract
Oncocytomas are distinct tumors characterized by an abnormal accumulation of defective and (most probably) dysfunctional mitochondria in cell cytoplasm of such tumors. This particular phenotype has been studied for the last decades and the clarification of the etiopathogenic causes are still needed. Several mechanisms involved in the formation and maintenance of oncocytomas are accepted as reasonable causes, but the relevance and contribution of each one for oncocytic transformation may depend on different cancer etiopathogenic contexts. In this review, we describe the current knowledge of the etiopathogenic events that may lead to oncocytic transformation and discuss their contribution for tumor progression and mitochondrial accumulation.
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Affiliation(s)
- Marcelo Correia
- Cancer Signalling and Metabolism Research Group, Instituto de Investigação e Inovação em Saúde - i3S (Institute for Research and Innovation in Health), University of Porto, Porto, Portugal; Cancer Signalling and Metabolism Research Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Pedro Pinheiro
- Cancer Signalling and Metabolism Research Group, Instituto de Investigação e Inovação em Saúde - i3S (Institute for Research and Innovation in Health), University of Porto, Porto, Portugal; Cancer Signalling and Metabolism Research Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Rui Batista
- Cancer Signalling and Metabolism Research Group, Instituto de Investigação e Inovação em Saúde - i3S (Institute for Research and Innovation in Health), University of Porto, Porto, Portugal; Cancer Signalling and Metabolism Research Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal
| | - Paula Soares
- Cancer Signalling and Metabolism Research Group, Instituto de Investigação e Inovação em Saúde - i3S (Institute for Research and Innovation in Health), University of Porto, Porto, Portugal; Cancer Signalling and Metabolism Research Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal; Department of Pathology, Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal
| | - Manuel Sobrinho-Simões
- Cancer Signalling and Metabolism Research Group, Instituto de Investigação e Inovação em Saúde - i3S (Institute for Research and Innovation in Health), University of Porto, Porto, Portugal; Cancer Signalling and Metabolism Research Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal; Department of Pathology, Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal; Department of Pathology, Centro Hospitalar São João, Porto, Portugal
| | - Valdemar Máximo
- Cancer Signalling and Metabolism Research Group, Instituto de Investigação e Inovação em Saúde - i3S (Institute for Research and Innovation in Health), University of Porto, Porto, Portugal; Cancer Signalling and Metabolism Research Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal; Department of Pathology, Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal.
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13
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Niedzwiecka K, Kabala AM, Lasserre JP, Tribouillard-Tanvier D, Golik P, Dautant A, di Rago JP, Kucharczyk R. Yeast models of mutations in the mitochondrial ATP6 gene found in human cancer cells. Mitochondrion 2016; 29:7-17. [PMID: 27083309 DOI: 10.1016/j.mito.2016.04.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 04/08/2016] [Accepted: 04/08/2016] [Indexed: 01/09/2023]
Abstract
Since the discovery of somatic mtDNA mutations in tumor cells, multiple studies have focused on establishing a causal relationship between those changes and alterations in energy metabolism, a hallmark of cancer cells. Yet the consequences of these mutations on mitochondrial function remain largely unknown. In this study, Saccharomyces cerevisiae has been used as a model to investigate the functional consequences of four cancer-associated missense mutations (8914C>A, 8932C>T, 8953A>G, 9131T>C) found in the mitochondrial MT-ATP6 gene. This gene encodes the a-subunit of F1FO-ATP synthase, which catalyzes the last steps of ATP production in mitochondria. Although the four studied mutations affected well-conserved residues of the a-subunit, only one of them (8932C>T) had a significant impact on mitochondrial function, due to a less efficient incorporation of the a-subunit into ATP synthase. Our findings indicate that these ATP6 genetic variants found in human tumors are neutral mitochondrial genome substitutions with a limited, if any, impact on the energetic function of mitochondria.
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Affiliation(s)
- Katarzyna Niedzwiecka
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Anna Magdalena Kabala
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université de Bordeaux, 1 rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France
| | - Jean-Paul Lasserre
- Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université de Bordeaux, 1 rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France
| | - Déborah Tribouillard-Tanvier
- Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université de Bordeaux, 1 rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France
| | - Pawel Golik
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Poland
| | - Alain Dautant
- Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université de Bordeaux, 1 rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France
| | - Jean-Paul di Rago
- Institut de Biochimie et Génétique Cellulaires, CNRS UMR5095, Université de Bordeaux, 1 rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France
| | - Roza Kucharczyk
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
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14
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Müller-Höcker J, Schäfer S, Krebs S, Blum H, Zsurka G, Kunz WS, Prokisch H, Seibel P, Jung A. Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 184:2922-35. [PMID: 25418474 DOI: 10.1016/j.ajpath.2014.07.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 07/14/2014] [Accepted: 07/17/2014] [Indexed: 02/01/2023]
Abstract
Oxyphil cell transformation of epithelial cells due to the accumulation of mitochondria occurs often during cellular aging. To understand the pathogenic mechanisms, we studied mitochondrial DNA (mtDNA) alterations in the three cell types of the parathyroids using multiplex real-time PCR and next-generation sequencing. mtDNA was analyzed from cytochrome c oxidase (COX)-positive and COX-negative areas of 19 parathyroids. Mitochondria-rich pre-oxyphil/oxyphil cells were more prone to develop COX defects than the mitochondria-poor clear chief cells (P < 0.001). mtDNA increased approximately 2.5-fold from clear chief to oxyphil cells. In COX deficiency, the increase was even more pronounced, and COX-negative oxyphil cells had approximately two times more mtDNA than COX-positive oxyphil cells (P < 0.001), illustrating the influence of COX deficiency on mtDNA biosynthesis, probably as a consequence of insufficient ATP synthesis. Next-generation sequencing revealed a broad spectrum of putative pathogenic mtDNA point mutations affecting NADH dehydrogenase and COX genes as well as regulatory elements of mtDNA. NADH dehydrogenase gene mutations preferentially accumulated in COX-positive pre-oxyphil/oxyphil cells and, therefore, could be essential for inducing oxyphil cell transformation by increasing mtDNA/mitochondrial biogenesis. In contrast, COX-negative cells predominantly harbored mutations in the MT-CO1 and MT-CO3 genes and in regulatory mtDNA elements, but only rarely NADH dehydrogenase mutations. Thus, multiple hits in NADH dehydrogenase and COX activity-impairing genes represent the molecular basis of oxyphil cell transformation in the parathyroids.
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Affiliation(s)
- Josef Müller-Höcker
- Institute for Pathology of the Ludwig-Maximilians-Universität München, Munich, Germany
| | - Sabine Schäfer
- Institute for Pathology of the Ludwig-Maximilians-Universität München, Munich, Germany
| | - Stefan Krebs
- Gene Center of the Ludwig-Maximilians-Universität München, Campus Großhadern, Munich, Germany
| | - Helmut Blum
- Gene Center of the Ludwig-Maximilians-Universität München, Campus Großhadern, Munich, Germany
| | - Gábor Zsurka
- Division of Neurochemistry, Department of Epileptology and Life and Brain Center, University of Bonn, Bonn, Germany
| | - Wolfram S Kunz
- Division of Neurochemistry, Department of Epileptology and Life and Brain Center, University of Bonn, Bonn, Germany
| | - Holger Prokisch
- Institute of Human Genetics, Helmholtz-Zentrum München, Neuherberg, Germany
| | - Peter Seibel
- Molekulare Zellbiologie, Biotechnological Biomedical Center, Universität Leipzig, Leipzig, Germany
| | - Andreas Jung
- Institute for Pathology of the Ludwig-Maximilians-Universität München, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany.
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Kim A. Mitochondrial DNA somatic mutation in cancer. Toxicol Res 2015; 30:235-42. [PMID: 25584142 PMCID: PMC4289923 DOI: 10.5487/tr.2014.30.4.235] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 12/20/2014] [Accepted: 12/23/2014] [Indexed: 12/31/2022] Open
Abstract
Cancer cells are known to drastically alter cellular energy metabolism. The Warburg effect has been known for over 80 years as pertaining cancer-specific aerobic glycolysis. As underlying molecular mechanisms are elucidated so that cancer cells alter the cellular energy metabolism for their advantage, the significance of the modulation of metabolic profiles is gaining attention. Now, metabolic reprogramming is becoming an emerging hallmark of cancer. Therapeutic agents that target cancer energy metabolism are under intensive investigation, but these investigations are mostly focused on the cytosolic glycolytic processes. Although mitochondrial oxidative phosphorylation is an integral part of cellular energy metabolism, until recently, it has been regarded as an auxiliary to cytosolic glycolytic processes in cancer energy metabolism. In this review, we will discuss the importance of mitochondrial respiration in the metabolic reprogramming of cancer, in addition to discussing the justification for using mitochondrial DNA somatic mutation as metabolic determinants for cancer sensitivity in glucose limitation.
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Affiliation(s)
- Aekyong Kim
- School of Pharmacy, Catholic University of Daegu, Gyeongbuk, Korea
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16
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Lee HC, Huang KH, Yeh TS, Chi CW. Somatic alterations in mitochondrial DNA and mitochondrial dysfunction in gastric cancer progression. World J Gastroenterol 2014; 20:3950-3959. [PMID: 24744584 PMCID: PMC3983450 DOI: 10.3748/wjg.v20.i14.3950] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 12/26/2013] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
Energy metabolism reprogramming was recently identified as one of the cancer hallmarks. One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA (mtDNA). In the past decades, several types of somatic mtDNA alterations have been identified in gastric cancer. However, the role of these mtDNA alterations in gastric cancer progression remains unclear. In this review, we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer. The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed. We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers. The two primary mutation types (transition mutations and mononucleotide or dinucleotide repeat instability) imply potential causative factors. Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer. The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies.
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Costa-Guda J, Arnold A. Genetic and epigenetic changes in sporadic endocrine tumors: parathyroid tumors. Mol Cell Endocrinol 2014; 386:46-54. [PMID: 24035866 PMCID: PMC3943641 DOI: 10.1016/j.mce.2013.09.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 09/03/2013] [Accepted: 09/03/2013] [Indexed: 01/05/2023]
Abstract
Parathyroid neoplasia is most commonly due to benign parathyroid adenoma but rarely can be caused by malignant parathyroid carcinoma. Evidence suggests that parathyroid carcinomas rarely, if ever, evolve through an identifiable benign intermediate, with the notable exception of carcinomas associated with the familial hyperparathyroidism-jaw tumor syndrome. Several genes have been directly implicated in the pathogenesis of typical sporadic parathyroid adenoma; somatic mutations in the MEN1 tumor suppressor gene are the most frequent finding, and alterations in the cyclin D1/PRAD1 oncogene are also firmly established molecular drivers of sporadic adenomas. In addition, good evidence supports mutation in the CDKN1B/p27 cyclin-dependent kinase inhibitor (CDKI) gene, and in other CDKI genes as contributing to disease pathogenesis in this context. Somatic defects in additional genes, including β-catenin, POT1 and EZH2 may contribute to parathyroid adenoma formation but, for most, their ability to drive parathyroid tumorigenesis remains to be demonstrated experimentally. Further, genetic predisposition to sporadic presentations of parathyroid adenoma appears be conferred by rare, and probably low-penetrance, germline variants in CDKI genes and, perhaps, in other genes such as CASR and AIP. The HRPT2 tumor suppressor gene is commonly mutated in parathyroid carcinoma.
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Affiliation(s)
- Jessica Costa-Guda
- Center for Molecular Medicine and Division of Endocrinology & Metabolism, University of Connecticut School of Medicine, Farmington, CT 06030-3101, USA
| | - Andrew Arnold
- Center for Molecular Medicine and Division of Endocrinology & Metabolism, University of Connecticut School of Medicine, Farmington, CT 06030-3101, USA.
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18
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Máximo V, Rios E, Sobrinho-Simões M. Oncocytic Lesions of the Thyroid, Kidney, Salivary Glands, Adrenal Cortex, and Parathyroid Glands. Int J Surg Pathol 2014; 22:33-6. [DOI: 10.1177/1066896913517938] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Oncocytic cell represents a special phenotype of neoplastic cells reflecting a unique biologic process characterized by the huge proliferation of morphologically abnormal mitochondria in the cytoplasm of neoplastic cells. This phenotype is driven by quite specific molecular mechanisms that interfere with mitochondrial function and metabolism. The oncocytic phenotype is more common in tumors arising in tissues presenting low proliferative rate, such as thyroid, kidney, salivary glands, adrenal cortex, and parathyroid glands, and it is superimposed on the genotypic and conventional histologic features of the tumors. In this short review, we address the similarity of the molecular alterations and of the biological features of the neoplastic cells in the oncocytic tumors of the different organs. We also discuss the differential diagnosis of benign and malignant oncocytic tumors as well as the prognosis of the malignant ones. We conclude that this rather unique phenotype, which is observed in tumors from different organs, indicates common metabolic alterations that may represent a useful target for therapeutic purposes.
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Affiliation(s)
- Valdemar Máximo
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Medical Faculty of the University of Porto, Porto, Portugal
| | - Elisabete Rios
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Medical Faculty of the University of Porto, Porto, Portugal
- Centro Hospitalar S. João, Porto, Portugal
| | - Manuel Sobrinho-Simões
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Medical Faculty of the University of Porto, Porto, Portugal
- Centro Hospitalar S. João, Porto, Portugal
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19
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Marucci G, Maresca A, Caporali L, Farnedi A, Betts CM, Morandi L, de Biase D, Cerasoli S, Foschini MP, Bonora E, Vidone M, Romeo G, Perli E, Giordano C, d'Amati G, Gasparre G, Baruzzi A, Carelli V, Eusebi V. Oncocytic glioblastoma: a glioblastoma showing oncocytic changes and increased mitochondrial DNA copy number. Hum Pathol 2013; 44:1867-1876. [PMID: 23664543 DOI: 10.1016/j.humpath.2013.02.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 02/23/2013] [Accepted: 02/28/2013] [Indexed: 02/05/2023]
Abstract
Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear to multinuclear cells and abundant, granular, eosinophilic cytoplasm. The cytoplasm of these same cells was filled by strongly immunoreactive mitochondria. At ultrastructure, numerous mitochondria, some of which were large, were evidenced in the cytoplasm of neoplastic cells. Finally, 9 of 10 of these cases had a significantly high mitochondrial DNA content compared with control tissue (P < .01). It seems that, for these tumors, the designation of oncocytic glioblastoma is appropriate. To the best of our knowledge, oncocytic changes have not been previously reported in such neoplasms. Oncocytic glioblastomas have to be added to the long list of various tumors that can manifest "unexpected" oncocytic changes in different organs. Albeit failing to show statistical significance (log-rank test, P = .597; Wilcoxon test, P = .233), we observed a trend for longer median survival in oncocytic glioblastomas, when compared with "ordinary" glioblastomas (median survival of 16 versus 8.7 months). Thus, it seems that the definition of neoplasms showing oncocytic changes, currently based on classic morphological parameters (ie, histology, ultrastructure, and immunohistochemistry), can be expanded by including the quantitative assessment of mitochondrial DNA content.
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Affiliation(s)
- Gianluca Marucci
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Section of Pathology, M. Malpighi, Bellaria Hospital, via Altura 3, 40139 Bologna, Italy
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Gasparre G, Porcelli AM, Lenaz G, Romeo G. Relevance of mitochondrial genetics and metabolism in cancer development. Cold Spring Harb Perspect Biol 2013; 5:5/2/a011411. [PMID: 23378588 DOI: 10.1101/cshperspect.a011411] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron transfer chain or to direct alterations of the mitochondrial respiratory complexes. In some cases, the depression of respiratory activity is clearly the consequence of disruptive mitochondrial DNA (mtDNA) mutations and leads as a consequence to enhanced generation of reactive oxygen species (ROS). By acting both as mutagens and cellular mitogens, ROS may contribute directly to cancer progression. On the basis of our experimental evidence, we suggest a deep implication of the supercomplex organization of the respiratory chain as a missing link between oxidative stress, energy failure, and tumorigenesis. We speculate that under conditions of oxidative stress, a dissociation of mitochondrial supercomplexes occurs, with destabilization of complex I and secondary enhanced generation of ROS, thus leading to a vicious circle amplifying mitochondrial dysfunction. An excellent model to dissect the role of pathogenic, disassembling mtDNA mutations in tumor progression and their contribution to the metabolic reprogramming of cancer cells (glycolysis vs. respiration) is provided by an often underdiagnosed subset of tumors, namely, the oncocytomas, characterized by disruptive mutations of mtDNA, especially of complex I subunits. Such mutations almost completely abolish complex I activity, which slows down the Krebs cycle, favoring a high ratio of α-ketoglutarate/succinate and consequent destabilization of hypoxia inducible factor 1α (HIF1α). On the other hand, if complex I is partially defective, the levels of NAD(+) may be sufficient to implement the Krebs cycle with higher levels of intermediates that stabilize HIF1α, thus favoring tumor malignancy. The threshold model we propose, based on the population-like dynamics of mitochondrial genetics (heteroplasmy vs. homoplasmy), implies that below threshold complex I is present and functioning correctly, thus favoring tumor growth, whereas above threshold, when complex I is not assembled, tumor growth is arrested. We have therefore termed "oncojanus" the mtDNA genes whose disruptive mutations have such a double-edged effect.
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Affiliation(s)
- Giuseppe Gasparre
- Department of Medical and Surgical Sciences, Unit of Medical Genetics, University of Bologna Medical School, 40138 Bologna, Italy
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21
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Hibi Y, Kambe F, Imai T, Ogawa K, Shimizu Y, Shibata M, Kagawa C, Mizuno Y, Ito A, Iwase K. Increased protein kinase A type Iα regulatory subunit expression in parathyroid gland adenomas of patients with primary hyperparathyroidism. Endocr J 2013. [PMID: 23197043 DOI: 10.1507/endocrj.ej12-0267] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Protein kinase A (PKA) regulatory subunit type Iα (RIα) is a major regulatory subunit that functions as an inhibitor of PKA kinase activity. We have previously demonstrated that elevated RIα expression is associated with diffuse-to-nodular transformation of hyperplasia in parathyroid glands of renal hyperparathyroidism. The aim of the current study was to determine whether or not RIα expression is increased in adenomas of primary hyperparathyroidism (PHPT), because monoclonal proliferation has been demonstrated in both adenomas and nodular hyperplasia. Surgical specimens comprising 22 adenomas and 11 normal glands, obtained from 22 patients with PHPT, were analyzed. Western blot and immunohistochemical analyses were employed to evaluate RIα expression. PKA activities were determined in several adenomas highly expressing RIα. RIα expression was also separately evaluated in chief and oxyphilic cells using the "Allred score" system. Expression of proliferating cell nuclear antigen (PCNA), a proliferation marker, was also immunohistochemically examined. Western blot analysis revealed that 5 out of 8 adenomas highly expressed RIα, compared with normal glands. PKA activity in adenomas was significantly less than in normal glands. Immunohistochemical analysis further demonstrated high expression of RIα in 20 out of 22 adenomas. In adenomas, the greater RIα expression and more PCNA positive cells were observed in both chief and oxyphilic cells. The present study suggested that high RIα expression could contribute to monoclonal proliferation of parathyroid cells by impairing the cAMP/PKA signaling pathway.
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Affiliation(s)
- Yatsuka Hibi
- Department of Endocrine Surgery, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.
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22
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Iommarini L, Calvaruso MA, Kurelac I, Gasparre G, Porcelli AM. Complex I impairment in mitochondrial diseases and cancer: Parallel roads leading to different outcomes. Int J Biochem Cell Biol 2013; 45:47-63. [DOI: 10.1016/j.biocel.2012.05.016] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 05/03/2012] [Accepted: 05/24/2012] [Indexed: 02/06/2023]
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23
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Pereira L, Soares P, Máximo V, Samuels DC. Somatic mitochondrial DNA mutations in cancer escape purifying selection and high pathogenicity mutations lead to the oncocytic phenotype: pathogenicity analysis of reported somatic mtDNA mutations in tumors. BMC Cancer 2012; 12:53. [PMID: 22299657 PMCID: PMC3342922 DOI: 10.1186/1471-2407-12-53] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 02/02/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The presence of somatic mitochondrial DNA (mtDNA) mutations in cancer cells has been interpreted in controversial ways, ranging from random neutral accumulation of mutations, to positive selection for high pathogenicity, or conversely to purifying selection against high pathogenicity variants as occurs at the population level. METHODS Here we evaluated the predicted pathogenicity of somatic mtDNA mutations described in cancer and compare these to the distribution of variations observed in the global human population and all possible protein variations that could occur in human mtDNA. We focus on oncocytic tumors, which are clearly associated with mitochondrial dysfunction. The protein variant pathogenicity was predicted using two computational methods, MutPred and SNPs&GO. RESULTS The pathogenicity score of the somatic mtDNA variants were significantly higher in oncocytic tumors compared to non-oncocytic tumors. Variations in subunits of Complex I of the electron transfer chain were significantly more common in tumors with the oncocytic phenotype, while variations in Complex V subunits were significantly more common in non-oncocytic tumors. CONCLUSIONS Our results show that the somatic mtDNA mutations reported over all tumors are indistinguishable from a random selection from the set of all possible amino acid variations, and have therefore escaped the effects of purifying selection that act strongly at the population level. We show that the pathogenicity of somatic mtDNA mutations is a determining factor for the oncocytic phenotype. The opposite associations of the Complex I and Complex V variants with the oncocytic and non-oncocytic tumors implies that low mitochondrial membrane potential may play an important role in determining the oncocytic phenotype.
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Affiliation(s)
- Luísa Pereira
- Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA
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24
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Abstract
Mitochondria are ubiquitous organelles in eukaryotic cells principally responsible for regulating cellular energy metabolism, free radical production, and the execution of apoptotic pathways. Abnormal oxidative phosphorylation (OXPHOS) and aerobic metabolism as a result of mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. In the past decades, numerous somatic mutations in both the coding and control regions of mitochondrial DNA (mtDNA) have been extensively examined in a broad range of primary human cancers, underscoring that accumulation of mtDNA alterations may be a critical factor in eliciting persistent mitochondrial defects and consequently contributing to cancer initiation and progression. However, the roles of these mtDNA mutations in the carcinogenic process remain largely unknown. This review outlines a wide variety of somatic mtDNA mutations identified in common human malignancies and highlights recent advances in understanding the causal roles of mtDNA variations in neoplastic transformation and tumor progression. In addition, it briefly illustrates how mtDNA alterations activate mitochondria-to-nucleus retrograde signaling so as to modulate the expression of relevant nuclear genes or induce epigenetic changes and promote malignant phenotypes in cancer cells. The present state of our knowledge regarding how mutational changes in the mitochondrial genome could be used as a diagnostic biomarker for early detection of cancer and as a potential target in the development of new therapeutic approaches is also discussed. These findings strongly indicate that mtDNA mutations exert a crucial role in the pathogenic mechanisms of tumor development, but continued investigations are definitely required to further elucidate the functional significance of specific mtDNA mutations in the etiology of human cancers.
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Jandova J, Eshaghian A, Shi M, Li M, King LE, Janda J, Sligh JE. Identification of an mtDNA mutation hot spot in UV-induced mouse skin tumors producing altered cellular biochemistry. J Invest Dermatol 2011; 132:421-8. [PMID: 22011905 PMCID: PMC3258376 DOI: 10.1038/jid.2011.320] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
There is increasing awareness of the role of mtDNA alterations in the development of cancer, as mtDNA point mutations are found at high frequency in a variety of human tumors. To determine the biological effects of mtDNA mutations in UV-induced skin tumors, hairless mice were irradiated to produce tumors, and the tumor mtDNAs were screened for single-nucleotide changes using temperature gradient capillary electrophoresis (TGCE), followed by direct sequencing. A mutation hot spot (9821insA) in the mitochondrially encoded tRNA arginine (mt-Tr) locus (tRNA(Arg)) was discovered in approximately one-third of premalignant and malignant skin tumors. To determine the functional relevance of this particular mutation in vitro, cybrid cell lines containing different mt-Tr (tRNA(Arg)) alleles were generated. The resulting cybrid cell lines contained the same nuclear genotype and differed only in their mtDNAs. The biochemical analysis of the cybrids revealed that the mutant haplotype is associated with diminished levels of complex I protein (CI), resulting in lower levels of baseline oxygen consumption and lower cellular adenosine triphosphate (ATP) production. We hypothesize that this specific mtDNA mutation alters cellular biochemistry, supporting the development of keratinocyte neoplasia.
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Affiliation(s)
- Jana Jandova
- Department of Medicine, Dermatology Division, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA
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26
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Gasparre G, Kurelac I, Capristo M, Iommarini L, Ghelli A, Ceccarelli C, Nicoletti G, Nanni P, De Giovanni C, Scotlandi K, Betts CM, Carelli V, Lollini PL, Romeo G, Rugolo M, Porcelli AM. A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an oncojanus function. Cancer Res 2011; 71:6220-9. [PMID: 21852384 DOI: 10.1158/0008-5472.can-11-1042] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The oncogenic versus suppressor roles of mitochondrial genes have long been debated. Peculiar features of mitochondrial genetics such as hetero/homoplasmy and mutation threshold are seldom taken into account in this debate. Mitochondrial DNA (mtDNA) mutations generally have been claimed to be protumorigenic, but they are also hallmarks of mostly benign oncocytic tumors wherein they help reduce adaptation to hypoxia by destabilizing hypoxia-inducible factor-1α (HIF1α). To determine the influence of a disassembling mtDNA mutation and its hetero/homoplasmy on tumorigenic and metastatic potential, we injected mice with tumor cells harboring different loads of the gene MTND1 m.3571insC. Cell cultures obtained from tumor xenografts were then analyzed to correlate energetic competence, apoptosis, α-ketoglutarate (α-KG)/succinate (SA) ratio, and HIF1α stabilization with the mutation load. A threshold level for the antitumorigenic effect of MTND1 m.3571insC mutation was defined, above which tumor growth and invasiveness were reduced significantly. Notably, HIF1α destabilization and downregulation of HIF1α-dependent genes occurred in cells and tumors lacking complex I (CI), where there was an associated imbalance of α-KG/SA despite the presence of an actual hypoxic environment. These results strongly implicate mtDNA mutations as a cause of oncocytic transformation. Thus, the antitumorigenic and antimetastatic effects of high loads of MTND1 m.3571insC, following CI disassembly, define a novel threshold-regulated class of cancer genes. We suggest these genes be termed oncojanus genes to recognize their ability to contribute either oncogenic or suppressive functions in mitochondrial settings during tumorigenesis.
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Affiliation(s)
- Giuseppe Gasparre
- Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, Genetica Medica, Università di Bologna, Italy
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Searching for a needle in the haystack: comparing six methods to evaluate heteroplasmy in difficult sequence context. Biotechnol Adv 2011; 30:363-71. [PMID: 21689740 DOI: 10.1016/j.biotechadv.2011.06.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Revised: 05/27/2011] [Accepted: 06/01/2011] [Indexed: 12/23/2022]
Abstract
Mitochondrial DNA (mtDNA) mutations have been involved in disease, aging and cancer and furthermore exploited for evolutionary and forensic investigation. When investigating mtDNA mutations the peculiar aspects of mitochondrial genetics, such as heteroplasmy and threshold effect, require suitable approaches which must be sensitive enough to detect low-level heteroplasmy and, precise enough to quantify the exact mutational load. In order to establish the optimal approach for the evaluation of heteroplasmy, six methods were experimentally compared for their capacity to reveal and quantify mtDNA variants. Drawbacks and advantages of cloning, Fluorescent PCR (F-PCR), denaturing High Performance Liquid Chromatography (dHPLC), quantitative Real-Time PCR (qRTPCR), High Resolution Melting (HRM) and 454 pyrosequencing were determined. In particular, detection and quantification of a mutation in a difficult sequence context were investigated, through analysis of an insertion in a homopolymeric stretch (m.3571insC).
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Gasparre G, Romeo G, Rugolo M, Porcelli AM. Learning from oncocytic tumors: Why choose inefficient mitochondria? BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2011; 1807:633-42. [DOI: 10.1016/j.bbabio.2010.08.006] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Revised: 08/09/2010] [Accepted: 08/15/2010] [Indexed: 10/19/2022]
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Guerra F, Kurelac I, Cormio A, Zuntini R, Amato LB, Ceccarelli C, Santini D, Cormio G, Fracasso F, Selvaggi L, Resta L, Attimonelli M, Gadaleta MN, Gasparre G. Placing mitochondrial DNA mutations within the progression model of type I endometrial carcinoma. Hum Mol Genet 2011; 20:2394-405. [DOI: 10.1093/hmg/ddr146] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Starker LF, Delgado-Verdugo A, Udelsman R, Björklund P, Carling T. Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism. Endocrine 2010; 38:397-401. [PMID: 20972721 DOI: 10.1007/s12020-010-9399-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 08/24/2010] [Indexed: 11/30/2022]
Abstract
To investigate the SDHAF2 gene and its effect on primary hyperparathyroidism. Parathyroid tumors causing primary hyperparathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in parathyroid tumors occurring in about 40% of sporadic tumors. Only 15-19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in parathyroid tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 parathyroid tumors but no tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in parathyroid tissue. However, somatic mutations of the SDHAF2 tumor suppressor gene are unlikely to frequently contribute to parathyroid tumor development in sporadic pHPT.
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Affiliation(s)
- Lee F Starker
- Department of Surgery, Yale University School of Medicine, 333 Cedar Street, TMP202, Box 208062, New Haven, CT 06520, USA
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Lee HC, Chang CM, Chi CW. Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 2010; 9 Suppl 1:S47-S58. [PMID: 20816876 DOI: 10.1016/j.arr.2010.08.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mitochondria are intracellular organelles responsible for generating ATP through respiration and oxidative phosphorylation (OXPHOS), producing reactive oxygen species, and initiating and executing apoptosis. Mitochondrial dysfunction has been observed to be an important hallmark of aging and cancer. Because mitochondrial DNA (mtDNA) is important in maintaining functionally competent organelles, accumulation of mtDNA mutations can affect energy production, oxidative stress, and cell survival, which may contribute to aging and/or carcinogenesis. This review outlines a variety of somatic mtDNA mutations identified in aging tissues and human cancers, as well as recent advances in understanding the causal role of mtDNA mutations in the aging process and cancer progression. Mitochondrial dysfunction elicited by somatic mutations in mtDNA could induce apoptosis in aging cells and some cancer cells with severe mtDNA mutations. In addition, it could activate mitochondria-to-nucleus retrograde signaling to modulate the expression of nuclear genes involved in a metabolic shift from OXPHOS to glycolysis, facilitate cells to adapt to altered environments and develop resistance to chemotherapeutic agents, or promote metastatic properties of cancer cells. These findings suggest that accumulation of somatic mtDNA mutations is not only an important contributor to human aging but also plays a critical role in cancer progression.
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Affiliation(s)
- Hsin-Chen Lee
- Institute of Pharmacology, School of Medicine, National Yang-Ming University, No 155, Sec 2, Li-Nong St, Peitou, Taipei 112, Taiwan, ROC.
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Mitochondrial cardiomyopathies: how to identify candidate pathogenic mutations by mitochondrial DNA sequencing, MITOMASTER and phylogeny. Eur J Hum Genet 2010; 19:200-7. [PMID: 20978534 PMCID: PMC3025796 DOI: 10.1038/ejhg.2010.169] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. Owing to a high mutation rate, mtDNA defects may occur at any nucleotide in its 16 569 bp sequence. Complete mtDNA sequencing may detect pathogenic mutations, which can be difficult to interpret because of normal ethnic/geographic-associated haplogroup variation. Our goal is to show how to identify candidate mtDNA mutations by sorting out polymorphisms using readily available online tools. The purpose of this approach is to help investigators in prioritizing mtDNA variants for functional analysis to establish pathogenicity. We analyzed complete mtDNA sequences from 29 Italian patients with mitochondrial cardiomyopathy or suspected disease. Using MITOMASTER and PhyloTree, we characterized 593 substitution variants by haplogroup and allele frequencies to identify all novel, non-haplogroup-associated variants. MITOMASTER permitted determination of each variant's location, amino acid change and evolutionary conservation. We found that 98% of variants were common or rare, haplogroup-associated variants, and thus unlikely to be primary cause in 80% of cases. Six variants were novel, non-haplogroup variants and thus possible contributors to disease etiology. Two with the greatest pathogenic potential were heteroplasmic, nonsynonymous variants: m.15132T>C in MT-CYB for a patient with hypertrophic dilated cardiomyopathy and m.6570G>T in MT-CO1 for a patient with myopathy. In summary, we have used our automated information system, MITOMASTER, to make a preliminary distinction between normal mtDNA variation and pathogenic mutations in patient samples; this fast and easy approach allowed us to select the variants for traditional analysis to establish pathogenicity.
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Genetic Predisposition to Familial Nonmedullary Thyroid Cancer: An Update of Molecular Findings and State-of-the-Art Studies. JOURNAL OF ONCOLOGY 2010; 2010:385206. [PMID: 20628519 PMCID: PMC2902056 DOI: 10.1155/2010/385206] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Revised: 02/09/2010] [Accepted: 04/01/2010] [Indexed: 02/07/2023]
Abstract
Familial thyroid cancer has become a well-recognized entity in patients with thyroid cancer
originating from follicular cells, that is, nonmedullary thyroid carcinoma. The diagnosis of
familial thyroid cancer provides an opportunity for early detection and possible prevention in
family members. Understanding the syndromes associated with familial thyroid cancer allows
clinicians to evaluate and treat patients for coexisting pathologic conditions. About five
percents of patients with well-differentiated thyroid carcinoma have a familial disease.
Patients with familial non-medullalry thyroid cancer have more aggressive tumors with
increased rates of extrathyroid extension, lymph node metastases, and frequently show the
phenomenon of “anticipation” (earlier age at disease onset and increased severity in
successive generations). So far, four predisposition loci have been identified in relatively rare
extended pedigrees, and association studies have identified multiple predisposing variants for
differentiated thyroid cancer. This suggests that there is a high degree of genetic
heterogeneity and that the development of this type of tumor is a multifactorial and complex
process in which predisposing genetic variants interact with a number of incompletely
understood environmental risk factors. Thus, the search for the causative variants is still open
and will surely benefit from the new technological approaches that have been developed in
recent years.
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Gasparre G, Bonora E, Tallini G, Romeo G. Molecular features of thyroid oncocytic tumors. Mol Cell Endocrinol 2010; 321:67-76. [PMID: 20184940 DOI: 10.1016/j.mce.2010.02.022] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Revised: 02/15/2010] [Accepted: 02/17/2010] [Indexed: 01/17/2023]
Abstract
Thyroid oncocytic neoplasms are tumors composed of cells characterized by an aberrant increase of mitochondrial mass. They represent a subset of thyroid tumors whose classification and clinical features has been a matter of controversy for clinicians and pathologists alike. The prevalence of oncocytic tumors in the thyroid gland, the relevance of the issues debated, and the obvious cellular derangement of oncocytic cells, namely a complete deregulation of the mitochondrial mass and metabolism, have spurred many investigators to study the molecular mechanism underlying the genesis of this peculiar cancer phenotype. Their findings, which are unraveling the tumor pathobiology, are the subject of the present review.
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Affiliation(s)
- Giuseppe Gasparre
- Dip. Scienze Ginecologiche, Ostetriche e Pediatriche, U.O. Genetica Medica, Pol. S.Orsola-Malpighi, Università di Bologna, Italy.
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Porcelli AM, Ghelli A, Ceccarelli C, Lang M, Cenacchi G, Capristo M, Pennisi LF, Morra I, Ciccarelli E, Melcarne A, Bartoletti-Stella A, Salfi N, Tallini G, Martinuzzi A, Carelli V, Attimonelli M, Rugolo M, Romeo G, Gasparre G. The genetic and metabolic signature of oncocytic transformation implicates HIF1alpha destabilization. Hum Mol Genet 2009; 19:1019-32. [PMID: 20028790 DOI: 10.1093/hmg/ddp566] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
We previously showed that disruptive complex I mutations in mitochondrial DNA are the main genetic hallmark of oncocytic tumors of the thyroid and kidney. We here report a high frequency of homoplasmic disruptive mutations in a large panel of oncocytic pituitary and head-and-neck tumors. The presence of such mutations implicates disassembly of respiratory complex I in vivo which in turn contributes to the inability of oncocytic tumors to stabilize HIF1alpha and to display pseudo-hypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), we induced the shift to homoplasmy of a truncating mutation in the mitochondria-coded MTND1 gene. Such shift is associated with a profound metabolic impairment leading to the imbalance of alpha-ketoglutarate and succinate, the Krebs cycle metabolites which are the main responsible for HIF1alpha stabilization. We conclude that the main hallmarks of oncocytic transformation, namely the occurrence of homoplasmic disruptive mutations and complex I disassembly, may explain the benign nature of oncocytic neoplasms through lack of HIF1alpha stabilization.
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Affiliation(s)
- Anna Maria Porcelli
- Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Bologna 40126, Italy
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36
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Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Res 2009; 19:802-15. [PMID: 19532122 DOI: 10.1038/cr.2009.69] [Citation(s) in RCA: 208] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Alterations in oxidative phosphorylation resulting from mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. Mitochondria have recently been shown to play an important role in regulating both programmed cell death and cell proliferation. Furthermore, mitochondrial DNA (mtDNA) mutations have been found in various cancer cells. However, the role of these mtDNA mutations in tumorigenesis remains largely unknown. This review focuses on basic mitochondrial genetics, mtDNA mutations and consequential mitochondrial dysfunction associated with cancer. The potential molecular mechanisms, mediating the pathogenesis from mtDNA mutations and mitochondrial dysfunction to tumorigenesis are also discussed.
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Gasparre G, Iommarini L, Porcelli AM, Lang M, Ferri GG, Kurelac I, Zuntini R, Mariani E, Pennisi LF, Pasquini E, Pasquinelli G, Ghelli A, Bonora E, Ceccarelli C, Rugolo M, Salfi N, Romeo G, Carelli V. An inherited mitochondrial DNA disruptive mutation shifts to homoplasmy in oncocytic tumor cells. Hum Mutat 2009; 30:391-6. [DOI: 10.1002/humu.20870] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Davenport C, Agha A. The role of menin in parathyroid tumorigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 668:79-86. [PMID: 20175455 DOI: 10.1007/978-1-4419-1664-8_8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary hyperparathyroidism is a common disorder that involves the pathological enlargement of one or more parathyroid glands resulting in excessive production of parathyroid hormone (PTH). The exact pathogenesis of this disease remains to be fully understood. In recent years interest has focussed on the interaction between menin protein and the transforming growth factor (TGF)-beta/Smad signalling pathway. In vitro experimentation has demonstrated that the presence of menin is required for TGF-beta to effectively inhibit parathyroid cell proliferation and PTH production. This observation correlates with the almost universal occurrence of parathyroid tumors accompanying the inactivation of menin in multiple endocrine neoplasia Type 1 (MEN1) syndrome and the high rate of somatic menin gene mutations seen in sporadic parathyroid adenomas. This chapter aims to review the role of menin in primary hyperparathyroidism and parathyroid hormone-regulation, including the influences of MEN1 gene mutations on parathyroid cell proliferation, differentiation and tumorigenesis.
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Affiliation(s)
- Colin Davenport
- Academic Department of Endocrinology, Beaumont Hospital and Royal College of Surgeons in Ireland Medical School, Beaumont Road, Dublin 9, Ireland
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