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Parchwani D, Singh R, Patel D. Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance. World J Methodol 2025; 15:102709. [DOI: 10.5662/wjm.v15.i3.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 01/21/2025] [Accepted: 02/08/2025] [Indexed: 03/06/2025] Open
Abstract
The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.
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Affiliation(s)
- Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Ragini Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Digisha Patel
- Department of Physiology, Shantabaa Medical College and General Hospital Amreli, Amreli 365601, Gujarāt, India
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Zhao X, Wu G, Tao X, Dong D, Liu J. Targeted mitochondrial therapy for pancreatic cancer. Transl Oncol 2025; 54:102340. [PMID: 40048984 PMCID: PMC11928980 DOI: 10.1016/j.tranon.2025.102340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/05/2025] [Accepted: 02/27/2025] [Indexed: 03/18/2025] Open
Abstract
Pancreatic cancer (PC) is a highly invasive tumor characterized by delayed diagnosis, rapid progress, and resistance to chemotherapy. Mitochondria, as the "power chamber" of cells, not only play a central role in energy metabolism but also participate in the production of reactive oxygen species (ROS), calcium signaling, regulation, and differentiation of the cell cycle. The abnormal activity of mitochondria is closely related to the development of PC. In this paper, we discussed the key role of mitochondria in PC, including mitochondrial DNA, mitochondrial biogenesis, mitochondrial dynamics, metabolic regulation, ROS generation, and mitochondrial-dependent apoptosis. We elaborated on the importance of these mitochondrial mechanisms in the development of PC and emphasized the potential of targeted mitochondrial therapy strategies for these mechanisms in the treatment of PC. In addition, this article also reviews the latest developments in innovative drug carriers such as cell-penetrating peptides, nucleic acid aptamers, and nanomaterials, which can achieve precise localization of mitochondria and drug delivery. Therefore, this article comprehensively analyzed the important role of mitochondria in the treatment of PC and clarified the effectiveness and necessity of targeting mitochondria in the treatment of PC.
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Affiliation(s)
- Xinya Zhao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Guoyu Wu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Jing Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
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Gonzalez Bosquet J, Wagner V, Polio A, Linder KE, Bender DP, Goodheart MJ, Schickling BM. Identification of Ovarian High-Grade Serous Carcinoma with Mitochondrial Gene Variation. Int J Mol Sci 2025; 26:1347. [PMID: 39941116 PMCID: PMC11818617 DOI: 10.3390/ijms26031347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/02/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
Women diagnosed with advanced-stage ovarian cancer have a much worse survival rate than women diagnosed with early-stage ovarian cancer, but the early detection of this disease remains a clinical challenge. Some recent reports indicate that genetic variations could be useful for the early detection of several malignancies. In this pilot observational retrospective study, we aimed to assess whether mitochondrial DNA (mtDNA) variations could discriminate the most frequent type of ovarian cancer, high-grade serous carcinoma (HGSC), from normal tissue. We identified mtDNA variations from 20 whole-exome sequenced (WES) HGSC samples and 14 controls (normal tubes) using the best practices of genome sequencing. We built prediction models of cancer with these variants, with good performance measured by the area under the curve (AUC) of 0.88 (CI: 0.74-1.00). The variants included in the best model were correlated with gene expression to assess the potentially affected processes. These analyses were validated with the Cancer Genome Atlas (TCGA) dataset, (including over 420 samples), with a fair performance in AUC terms (0.63-0.71). In summary, we identified a set of mtDNA variations that can discriminate HGSC with good performance. Specifically, variations in the MT-CYB gene increased the risk for HGSC by over 30%, and MT-CYB expression was significantly decreased in HGSC patients. Robust models of ovarian cancer detection with mtDNA variations could be applied to liquid biopsy technology, like those which have been applied to other cancers, with a special focus on the early detection of this lethal disease.
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Affiliation(s)
- Jesus Gonzalez Bosquet
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA (A.P.); (K.E.L.); (D.P.B.); (B.M.S.)
- Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Vincent Wagner
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA (A.P.); (K.E.L.); (D.P.B.); (B.M.S.)
| | - Andrew Polio
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA (A.P.); (K.E.L.); (D.P.B.); (B.M.S.)
| | - Katharine E. Linder
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA (A.P.); (K.E.L.); (D.P.B.); (B.M.S.)
| | - David P. Bender
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA (A.P.); (K.E.L.); (D.P.B.); (B.M.S.)
- Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Michael J. Goodheart
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA (A.P.); (K.E.L.); (D.P.B.); (B.M.S.)
- Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Brandon M. Schickling
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA (A.P.); (K.E.L.); (D.P.B.); (B.M.S.)
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Stocker H, Gentiluomo M, Trares K, Beyer L, Stevenson-Hoare J, Rujescu D, Holleczek B, Beyreuther K, Gerwert K, Schöttker B, Campa D, Canzian F, Brenner H. Mitochondrial DNA abundance in blood is associated with Alzheimer's disease- and dementia-risk. Mol Psychiatry 2025; 30:131-139. [PMID: 39009700 DOI: 10.1038/s41380-024-02670-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 06/22/2024] [Accepted: 07/08/2024] [Indexed: 07/17/2024]
Abstract
The mitochondrial cascade hypothesis of Alzheimer's disease (AD) has been portrayed through molecular, cellular, and animal studies; however large epidemiological studies are lacking. This study aimed to explore the association of mitochondrial DNA copy number (mtDNAcn), a marker representative of mtDNA abundance per cell, with risk of incident all-cause dementia, AD, and vascular dementia diagnosis within 17 years and dementia-related blood biomarkers (P-tau181, GFAP, and NfL). Additionally, sex-stratified analyses were completed. In this German population-based cohort study (ESTHER), 9940 participants aged 50-75 years were enrolled by general practitioners and followed for 17 years. Participants were included in this study if information on dementia status and blood-based mtDNAcn measured via real-time polymerase chain reaction were available. In a nested case-control approach, a subsample of participants additionally had measurements of P-tau181, GFAP, and NfL in blood samples taken at baseline. Of 4913 participants eligible for analyses, 386 were diagnosed with incident all-cause dementia, including 130 AD and 143 vascular dementia cases, while 4527 participants remained without dementia diagnosis within 17 years. Participants with low mtDNAcn (lowest 10%) experienced 45% and 65% percent increased risk of incident all-cause dementia and AD after adjusting for age and sex (all-cause dementia: HRadj, 95%CI:1.45, 1.08-1.94; AD: HRadj, 95%CI: 1.65, 1.01-2.68). MtDNAcn was not associated to vascular dementia diagnosis and was more strongly associated with all-cause dementia among women. In the nested case-control study (n = 790), mtDNAcn was not significantly associated with the dementia-related blood biomarkers (P-tau181, GFAP, and NfL) levels in blood from baseline before dementia diagnosis. This study provides novel epidemiological evidence connecting mtDNA abundance, measured via mtDNAcn, to incident dementia and AD at the population-based level. Reduced mitochondrial abundance may play a role in pathogenesis, especially among women.
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Affiliation(s)
- Hannah Stocker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
- Network Aging Research, Heidelberg University, Heidelberg, Germany.
| | | | - Kira Trares
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Léon Beyer
- Center for Protein Diagnostics (ProDi), Ruhr-University Bochum, Bochum, Germany
- Faculty of Biology and Biotechnology, Department of Biophysics, Ruhr-University Bochum, Bochum, Germany
| | - Joshua Stevenson-Hoare
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Dan Rujescu
- Department of Psychiatry, Medical University of Vienna, Vienna, Austria
| | | | | | - Klaus Gerwert
- Center for Protein Diagnostics (ProDi), Ruhr-University Bochum, Bochum, Germany
- Faculty of Biology and Biotechnology, Department of Biophysics, Ruhr-University Bochum, Bochum, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
| | - Federico Canzian
- Genomic Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
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Berner MJ, Wall SW, Echeverria GV. Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities. Br J Cancer 2024; 131:1415-1424. [PMID: 39143326 PMCID: PMC11519338 DOI: 10.1038/s41416-024-02817-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/16/2024] Open
Abstract
"Reprogramming of energy metabolism" was first considered an emerging hallmark of cancer in 2011 by Hanahan & Weinberg and is now considered a core hallmark of cancer. Mitochondria are the hubs of metabolism, crucial for energetic functions and cellular homeostasis. The mitochondrion's bacterial origin and preservation of their own genome, which encodes proteins and RNAs essential to their function, make them unique organelles. Successful generation of mitochondrial gene products requires coordinated functioning of the mitochondrial 'central dogma,' encompassing all steps necessary for mtDNA to yield mitochondrial proteins. Each of these processes has several levels of regulation, including mtDNA accessibility and protection through mtDNA packaging and epigenetic modifications, mtDNA copy number through mitochondrial replication, mitochondrial transcription through mitochondrial transcription factors, and mitochondrial translation through mitoribosome formation. Deregulation of these mitochondrial processes in the context of cancers has only recently been appreciated, with most studies being correlative in nature. Nonetheless, numerous significant associations of the mitochondrial central dogma with pro-tumor phenotypes have been documented. Several studies have even provided mechanistic insights and further demonstrated successful pharmacologic targeting strategies. Based on the emergent importance of mitochondria for cancer biology and therapeutics, it is becoming increasingly important that we gain an understanding of the underpinning mechanisms so they can be successfully therapeutically targeted. It is expected that this mechanistic understanding will result in mitochondria-targeting approaches that balance anticancer potency with normal cell toxicity. This review will focus on current evidence for the dysregulation of mitochondrial gene expression in cancers, as well as therapeutic opportunities on the horizon.
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Affiliation(s)
- Mariah J Berner
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Steven W Wall
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Gloria V Echeverria
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
- Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA.
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6
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Cai X, Liang C, Zhang M, Dong Z, Weng Y, Yu W. Mitochondrial DNA copy number and cancer risks: A comprehensive Mendelian randomization analysis. Int J Cancer 2024; 154:1504-1513. [PMID: 38151753 DOI: 10.1002/ijc.34833] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/27/2023] [Accepted: 12/11/2023] [Indexed: 12/29/2023]
Abstract
Mitochondrial DNA plays a critical role in the pathophysiology of cancer. However, the associations between mitochondrial DNA copy number (mtDNA-CN) and cancer risk are controversial. Mendelian randomization (MR) analyses were performed using three independent instrumental variables (IVs) to explore potential associations between mtDNA-CN and 20 types of cancer. The three sets of IVs were primarily obtained from participants in the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium using different methods. The outcome data of cancers were investigated using summary statistics from the FinnGen cohort. The potential causal associations were evaluated using the MR-Egger regression, weighted median, inverse-variance weighted (IVW), and weighted mode methods. The robustness of IVW estimates was validated using leave-one-out sensitivity analysis. Additionally, a meta-analysis was conducted to pool results from three sets of IVs. The results revealed that genetically predicted mtDNA-CN was not associated with cancer risk (odds ratio = 1.02; 95% confidence interval: 0.95-1.10). Subgroup analyses indicated no causal association between mtDNA-CN and breast, lung, prostate, skin, colorectal, gastric, liver, cervical uteri, esophageal, thyroid, bladder, pancreas, kidney, corpus uteri, ovary, brain, larynx, and anus cancers. It was observed that mtDNA-CN was associated with lip, oral cavity, and testis cancers. However, these results should be interpreted with caution because a small number of patients with lip and oral cavity or testis cancers were included. The comprehensive MR analysis demonstrated that mtDNA-CN is not a suitable biomarker for tumor risk assessment.
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Affiliation(s)
- Xianlei Cai
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University (Ningbo Medical Center Lihuili Hospital), Zhejiang, China
| | - Chao Liang
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University (Ningbo Medical Center Lihuili Hospital), Zhejiang, China
| | - Miaozun Zhang
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University (Ningbo Medical Center Lihuili Hospital), Zhejiang, China
| | - Zhebin Dong
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University (Ningbo Medical Center Lihuili Hospital), Zhejiang, China
| | - Yihui Weng
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University (Ningbo Medical Center Lihuili Hospital), Zhejiang, China
| | - Weiming Yu
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University (Ningbo Medical Center Lihuili Hospital), Zhejiang, China
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7
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Chi H, Su L, Yan Y, Gu X, Su K, Li H, Yu L, Liu J, Wang J, Wu Q, Yang G. Illuminating the immunological landscape: mitochondrial gene defects in pancreatic cancer through a multiomics lens. Front Immunol 2024; 15:1375143. [PMID: 38510247 PMCID: PMC10953916 DOI: 10.3389/fimmu.2024.1375143] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 02/16/2024] [Indexed: 03/22/2024] Open
Abstract
This comprehensive review delves into the complex interplay between mitochondrial gene defects and pancreatic cancer pathogenesis through a multiomics approach. By amalgamating data from genomic, transcriptomic, proteomic, and metabolomic studies, we dissected the mechanisms by which mitochondrial genetic variations dictate cancer progression. Emphasis has been placed on the roles of these genes in altering cellular metabolic processes, signal transduction pathways, and immune system interactions. We further explored how these findings could refine therapeutic interventions, with a particular focus on precision medicine applications. This analysis not only fills pivotal knowledge gaps about mitochondrial anomalies in pancreatic cancer but also paves the way for future investigations into personalized therapy options. This finding underscores the crucial nexus between mitochondrial genetics and oncological immunology, opening new avenues for targeted cancer treatment strategies.
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Affiliation(s)
- Hao Chi
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Lanqian Su
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Yalan Yan
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Xiang Gu
- Biology Department, Southern Methodist University, Dallas, TX, United States
| | - Ke Su
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Han Li
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Lili Yu
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China
| | - Jie Liu
- Department of General Surgery, Dazhou Central Hospital, Dazhou, China
| | - Jue Wang
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China
| | - Qibiao Wu
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China
| | - Guanhu Yang
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China
- Department of Specialty Medicine, Ohio University, Athens, OH, United States
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8
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Zhang W, Lin S, Zeng B, Chen X, Chen L, Chen M, Guo W, Lin Y, Yu L, Hou J, Li Y, Li S, Jin X, Cai W, Zhang K, Nie Q, Chen H, Li J, He P, Cai Q, Qiu Y, Wang C, Fu F. High leukocyte mitochondrial DNA copy number contributes to poor prognosis in breast cancer patients. BMC Cancer 2023; 23:377. [PMID: 37098487 PMCID: PMC10131463 DOI: 10.1186/s12885-023-10838-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/12/2023] [Indexed: 04/27/2023] Open
Abstract
BACKGROUND Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA copy number (mtDNAcn) and prognosis of several malignancies in a cancer-specific manner. However, whether leukocyte mtDNAcn can predict the clinical outcome of breast cancer (BC) patients has not been well investigated. METHODS The mtDNA copy number of peripheral blood leukocytes from 661 BC patients was measured using a Multiplex AccuCopy™Kit based on a multiplex fluorescence competitive PCR principle. Kaplan-Meier curves and Cox proportional hazards regression model were applied to investigate the association of mtDNAcn with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer special survival (BCSS), and overall survival (OS) of patients. The possible mtDNAcn-environment interactions were also evaluated by the Cox proportional hazard regression models. RESULTS BC patients with higher leukocyte mtDNA-CN exhibited a significantly worse iDFS than those with lower leukocyte mtDNAcn (5-year iDFS: fully-adjusted model: HR = 1.433[95%CI 1.038-1.978], P = 0.028). Interaction analyses showed that mtDNAcn was significantly associated with hormone receptor status (adjusted p for interaction: 5-year BCSS: 0.028, 5-year OS: 0.022), so further analysis was mainly in the HR subgroup. Multivariate Cox regression analysis demonstrated that mtDNAcn was an independent prognostic factor for both BCSS and OS in HR-positive patients (HR+: 5-year BCSS: adjusted HR (aHR) = 2.340[95% CI 1.163-4.708], P = 0.017 and 5-year OS: aHR = 2.446 [95% CI 1.218-4.913], P = 0.011). CONCLUSIONS For the first time, our study demonstrated that leukocyte mtDNA copy number might influence the outcome of early-stage breast cancer patients depending on intrinsic tumor subtypes in Chinese women.
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Grants
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2018Y9055 Joint Funds for the Innovation of Science and Technology, Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2019-WJ-23 Joint Key Funds for the Health and Education of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
- 2021J01737 Joint Key Funds for the Natural Science Foundation of Fujian Province
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Affiliation(s)
- Wenzhe Zhang
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Songping Lin
- Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Bangwei Zeng
- Nosocomial Infection Control Branch, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Xiaobin Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Lili Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Minyan Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Wenhui Guo
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Yuxiang Lin
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Liuwen Yu
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Jialin Hou
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Yan Li
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Shengmei Li
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Xuan Jin
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Weifeng Cai
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Kun Zhang
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Qian Nie
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Hanxi Chen
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Jing Li
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Peng He
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Qindong Cai
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Yibin Qiu
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Chuan Wang
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China.
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China.
| | - Fangmeng Fu
- Department of Breast Surgery, Fujian Medical University Union Hospital, No.29, Xin Quan Road, Gulou District, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian Province, China.
- Breast Cancer Institute, Fujian Medical University, Fuzhou, 350001, Fujian Province, China.
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9
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Sarwar A, Zhu M, Su Q, Zhu Z, Yang T, Chen Y, Peng X, Zhang Y. Targeting mitochondrial dysfunctions in pancreatic cancer evokes new therapeutic opportunities. Crit Rev Oncol Hematol 2022; 180:103858. [DOI: 10.1016/j.critrevonc.2022.103858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/07/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
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10
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Lou Q, Zhang M, Zhang K, Liu X, Zhang Z, Zhang X, Yang Y, Gao Y. Arsenic exposure elevated ROS promotes energy metabolic reprogramming with enhanced AKT-dependent HK2 expression. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 836:155691. [PMID: 35525345 DOI: 10.1016/j.scitotenv.2022.155691] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/22/2022] [Accepted: 04/30/2022] [Indexed: 06/14/2023]
Abstract
Exposure to inorganic or organic arsenic compounds continues to pose substantial public health concerns for hundreds of millions of people around the globe. Highly exposed individuals are susceptible to various illnesses, including impairments and cancers of the lung, liver, skin and bladder. Long-term exposure to low-dose arsenic has been identified to induce aerobic glycolysis, which contributes to cells aberrant proliferation. However, the mechanism underlying arsenic-induced aerobic glycolysis is still unclear. Here, mtDNA copy number is enhanced in arsenic-exposed populations and a positive correlation between serum HK2 and urinary total arsenic was observed in the individuals with high urine arsenic (≥ 0.032 mg/L). In a rat model of trivalent arsenic (iAs3+) exposure, the levels of HK2, NDUFA9 and NDUFB8 were increased in the rats treated with iAs3+ daily by gavage for 12 weeks than those in the control rats. Subsequently, in a low-dose arsenic exposure cell model we found that 0.2 μmol/L iAs3+ induced aerobic glycolysis to promote L-02 cells proliferation and inhibit apoptosis, in which HK2 played an important role. Further studies showed accumulated ROS determined the metabolic reprogramming via activating AKT and then increasing HK2 expression. On the one hand, activated AKT induced aerobic glycolysis by increasing HK2 to promote L-02 cells viability and DNA synthesis; on the other hand, phosphorylated AKT induced HK2 mitochondrial outer-membrane location with VDAC1 to inhibit apoptosis. Taken together, our results indicated that ROS induced by low-dose arsenic exposure determined energy metabolic reprogramming and acted a critical regulator for AKT-dependent HK2 expression and aerobic glycolysis.
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Affiliation(s)
- Qun Lou
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Meichen Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Kunyu Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Xiaona Liu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Zaihong Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Xin Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Yanmei Yang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
| | - Yanhui Gao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
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11
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Preanalytical Variables in the Analysis of Mitochondrial DNA in Whole Blood and Plasma from Pancreatic Cancer Patients. Diagnostics (Basel) 2022; 12:diagnostics12081905. [PMID: 36010255 PMCID: PMC9406772 DOI: 10.3390/diagnostics12081905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 02/07/2023] Open
Abstract
Given the crucial role of mitochondria as the main cellular energy provider and its contribution towards tumor growth, chemoresistance, and cancer cell plasticity, mitochondrial DNA (mtDNA) could serve as a relevant biomarker. Thus, the profiling of mtDNA mutations and copy number variations is receiving increasing attention for its possible role in the early diagnosis and monitoring therapies of human cancers. This applies particularly to highly aggressive pancreatic cancer, which is often diagnosed late and is associated with poor prognosis. As current diagnostic procedures are based on imaging, tissue histology, and protein biomarkers with rather low specificity, tumor-derived mtDNA mutations detected from whole blood represents a potential significant leap forward towards early cancer diagnosis. However, for future routine use in clinical settings it is essential that preanalytics related to the characterization of mtDNA in whole blood are thoroughly standardized, controlled, and subject to proper quality assurance, yet this is largely lacking. Therefore, in this study we carried out a comprehensive preanalytical workup comparing different mtDNA extraction methods and testing important preanalytical steps, such as the use of different blood collection tubes, different storage temperatures, length of storage time, and yields in plasma vs. whole blood. To identify analytical and preanalytical differences, all variables were tested in both healthy subjects and pancreatic carcinoma patients. Our results demonstrated a significant difference between cancer patients and healthy subjects for some preanalytical workflows, while other workflows failed to yield statistically significant differences. This underscores the importance of controlling and standardizing preanalytical procedures in the development of clinical assays based on the measurement of mtDNA.
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12
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Abd Radzak SM, Mohd Khair SZN, Ahmad F, Patar A, Idris Z, Mohamed Yusoff AA. Insights regarding mitochondrial DNA copy number alterations in human cancer (Review). Int J Mol Med 2022; 50:104. [PMID: 35713211 PMCID: PMC9304817 DOI: 10.3892/ijmm.2022.5160] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/26/2022] [Indexed: 11/25/2022] Open
Abstract
Mitochondria are the critical organelles involved in various cellular functions. Mitochondrial biogenesis is activated by multiple cellular mechanisms which require a synchronous regulation between mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). The mitochondrial DNA copy number (mtDNA-CN) is a proxy indicator for mitochondrial activity, and its alteration reflects mitochondrial biogenesis and function. Despite the precise mechanisms that modulate the amount and composition of mtDNA, which have not been fully elucidated, mtDNA-CN is known to influence numerous cellular pathways that are associated with cancer and as well as multiple other diseases. In addition, the utility of current technology in measuring mtDNA-CN contributes to its extensive assessment of diverse traits and tumorigenesis. The present review provides an overview of mtDNA-CN variations across human cancers and an extensive summary of the existing knowledge on the regulation and machinery of mtDNA-CN. The current information on the advanced methods used for mtDNA-CN assessment is also presented.
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Affiliation(s)
- Siti Muslihah Abd Radzak
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Siti Zulaikha Nashwa Mohd Khair
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Farizan Ahmad
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Azim Patar
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Zamzuri Idris
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
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13
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Arance E, Ramírez V, Rubio-Roldan A, Ocaña-Peinado FM, Romero-Cachinero C, Jódar-Reyes AB, Vazquez-Alonso F, Martinez-Gonzalez LJ, Alvarez-Cubero MJ. Determination of Exosome Mitochondrial DNA as a Biomarker of Renal Cancer Aggressiveness. Cancers (Basel) 2021; 14:cancers14010199. [PMID: 35008363 PMCID: PMC8750318 DOI: 10.3390/cancers14010199] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 12/23/2021] [Accepted: 12/28/2021] [Indexed: 01/12/2023] Open
Abstract
Simple Summary Components of liquid biopsy are potential non-invasive biomarkers for monitoring renal cell carcinoma (RCC) status. The aim of our study was to examine mitochondrial genes (such as HV1 and CYB) included in exosomal fractions as promising and innovative biomarkers in RCC. We found that phase C containing different types of vesicles and phase F rich in exosomes with a high mitochondrial DNA (mtDNA) content could be considered as powerful biomarkers for susceptibility to RCC. Interestingly, mtDNA was a good genetic marker when aggressiveness was evaluated. Abstract Here, the role of non-invasive biomarkers in liquid biopsy was evaluated, mainly in exosomes and mitochondrial DNA (mtDNA) as promising, novel, and stable biomarkers for renal cell carcinoma (RCC). A total of 140 fractions (named from B to F) obtained by ultracentrifugations of whole blood samples from 28 individuals (13 patients and 15 controls) were included. Nanoparticle Tracking Analysis (NTA) was conducted to characterized exosomal fraction. Subsequently, an analysis of digital PCR (dPCR) using the QuantStudio™ 3D Digital PCR platform was performed and the quantification of mtDNA copy number by QuantStudioTM 12K Flex Real-Time PCR System (qPCR) was developed. Moreover, Next Generation Sequencing (NGS) analyses were included using MiSeq system (Illumina, San Diego, CA, USA). An F fraction, which contains all exosome data and all mitochondrial markers, was identified in dPCR and qPCR with statistically significant power (adjusted p values ≤ 0.03) when comparing cases and controls. Moreover, present analysis in mtDNA showed a relevant significance in RCC aggressiveness. To sum up, this is the first time a relation between exosomal mtDNA markers and clinical management of RCC is analyzed. We suggest a promising strategy for future liquid biopsy RCC analysis, although more analysis should be performed prior to application in routine clinical practice.
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Affiliation(s)
- Elena Arance
- GENYO. Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada-Avenida de la Ilustración, 114-18016 Granada, Spain; (E.A.); (V.R.); (A.R.-R.)
| | - Viviana Ramírez
- GENYO. Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada-Avenida de la Ilustración, 114-18016 Granada, Spain; (E.A.); (V.R.); (A.R.-R.)
| | - Alejandro Rubio-Roldan
- GENYO. Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada-Avenida de la Ilustración, 114-18016 Granada, Spain; (E.A.); (V.R.); (A.R.-R.)
| | | | - Catalina Romero-Cachinero
- Nursery Department. University Hospital Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014 Granada, Spain;
| | - Ana Belén Jódar-Reyes
- Biocolloid and Fluid Physics Group, Excellence Research Unit Modeling Nature (MNat), Department of Applied Physics, School of Sciences, University of Granada, 18071 Granada, Spain;
| | - Fernando Vazquez-Alonso
- Urology Department, University Hospital Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014 Granada, Spain;
| | - Luis Javier Martinez-Gonzalez
- GENYO. Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada-Avenida de la Ilustración, 114-18016 Granada, Spain; (E.A.); (V.R.); (A.R.-R.)
- Correspondence: ; Tel.: +34-958-715-500; Fax: +34-958-637-071
| | - Maria Jesus Alvarez-Cubero
- Department of Biochemistry and Molecular Biology III, Faculty of Medicine, PTS Granada, University of Granada, 18016 Granada, Spain;
- Instituto de Investigación Biosanitaria ibs. GRANADA, 18014 Granada, Spain
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14
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Gentiluomo M, Giaccherini M, Gào X, Guo F, Stocker H, Schöttker B, Brenner H, Canzian F, Campa D. Genome-wide association study of mitochondrial copy number. Hum Mol Genet 2021; 31:1346-1355. [PMID: 34964454 DOI: 10.1093/hmg/ddab341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 10/27/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
Mitochondrial DNA copy number (mtDNAcn) variation has been associated with increased risk of several human diseases in epidemiological studies. The quantification of mtDNAcn performed with real-time PCR is currently considered the de facto standard among several techniques. However, the heterogeneity of the laboratory methods (DNA extraction, storage, processing) used could give rise to results that are difficult to compare and reproduce across different studies. Several lines of evidence suggest that mtDNAcn is influenced by nuclear and mitochondrial genetic variability, however this relation is largely unexplored. The aim of this work was to elucidate the genetic basis of mtDNAcn variation. We performed a genome-wide association study (GWAS) of mtDNAcn in 6836 subjects from the ESTHER prospective cohort, and included, as replication set, the summary statistics of a GWAS that used 295 150 participants from the UK Biobank. We observed two novel associations with mtDNAcn variation on chromosome 19 (rs117176661), and 12 (rs7136238) that reached statistical significance at the genome-wide level. A polygenic score that we called mitoscore including all known single nucleotide polymorphisms explained 1.11% of the variation of mtDNAcn (p = 5.93 × 10-7). In conclusion, we performed a GWAS on mtDNAcn, adding to the evidence of the genetic background of this trait.
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Affiliation(s)
- Manuel Gentiluomo
- Unit of Genetics, Department of Biology, University of Pisa, 56126, Italy
| | - Matteo Giaccherini
- Unit of Genetics, Department of Biology, University of Pisa, 56126, Italy.,Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Xīn Gào
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Feng Guo
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Hannah Stocker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.,Network Aging Research, Heidelberg University, Heidelberg, 69120, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.,Network Aging Research, Heidelberg University, Heidelberg, 69120, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.,Network Aging Research, Heidelberg University, Heidelberg, 69120, Germany.,Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, 69120, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, 69120, Germany
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Daniele Campa
- Unit of Genetics, Department of Biology, University of Pisa, 56126, Italy
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15
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Pérez-Amado CJ, Bazan-Cordoba A, Hidalgo-Miranda A, Jiménez-Morales S. Mitochondrial Heteroplasmy Shifting as a Potential Biomarker of Cancer Progression. Int J Mol Sci 2021; 22:7369. [PMID: 34298989 PMCID: PMC8304746 DOI: 10.3390/ijms22147369] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer.
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Affiliation(s)
- Carlos Jhovani Pérez-Amado
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
- Programa de Maestría y Doctorado, Posgrado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Amellalli Bazan-Cordoba
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
- Programa de Maestría y Doctorado, Posgrado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Alfredo Hidalgo-Miranda
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
| | - Silvia Jiménez-Morales
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico; (C.J.P.-A.); (A.B.-C.); (A.H.-M.)
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16
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Gentiluomo M, Luddi A, Cingolani A, Fornili M, Governini L, Lucenteforte E, Baglietto L, Piomboni P, Campa D. Telomere Length and Male Fertility. Int J Mol Sci 2021; 22:ijms22083959. [PMID: 33921254 PMCID: PMC8069448 DOI: 10.3390/ijms22083959] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/03/2021] [Accepted: 04/08/2021] [Indexed: 12/23/2022] Open
Abstract
Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a p < 0.05. Namely, ACYP2˗rs11125529 and decreased sperm motility (p = 0.03); PXK˗rs6772228 with a lower sperm count (p = 0.02); NAF1˗rs7675998 with increased probability of having abnormal acrosomes (p = 0.03) and abnormal flagellum (p = 0.04); ZNF208˗rs8105767 and reduction of sperms with normal heads (p = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.
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Affiliation(s)
- Manuel Gentiluomo
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.); (A.C.); (D.C.)
| | - Alice Luddi
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (L.G.)
| | - Annapaola Cingolani
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.); (A.C.); (D.C.)
| | - Marco Fornili
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.F.); (E.L.); (L.B.)
| | - Laura Governini
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (L.G.)
| | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.F.); (E.L.); (L.B.)
| | - Laura Baglietto
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.F.); (E.L.); (L.B.)
| | - Paola Piomboni
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (L.G.)
- Correspondence: ; Tel.: +39-057-758-6632
| | - Daniele Campa
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.); (A.C.); (D.C.)
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17
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Bagheri HS, Bani F, Tasoglu S, Zarebkohan A, Rahbarghazi R, Sokullu E. Mitochondrial donation in translational medicine; from imagination to reality. J Transl Med 2020; 18:367. [PMID: 32977804 PMCID: PMC7517067 DOI: 10.1186/s12967-020-02529-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023] Open
Abstract
The existence of active crosstalk between cells in a paracrine and juxtacrine manner dictates specific activity under physiological and pathological conditions. Upon juxtacrine interaction between the cells, various types of signaling molecules and organelles are regularly transmitted in response to changes in the microenvironment. To date, it has been well-established that numerous parallel cellular mechanisms participate in the mitochondrial transfer to modulate metabolic needs in the target cells. Since the conception of stem cells activity in the restoration of tissues’ function, it has been elucidated that these cells possess a unique capacity to deliver the mitochondrial package to the juxtaposed cells. The existence of mitochondrial donation potentiates the capacity of modulation in the distinct cells to achieve better therapeutic effects. This review article aims to scrutinize the current knowledge regarding the stem cell’s mitochondrial transfer capacity and their regenerative potential.
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Affiliation(s)
- Hesam Saghaei Bagheri
- School of Medicine, Biophysics Department, Koç University, Rumeli Fener, Sarıyer, Istanbul, Turkey.,Koç University Translational Medicine Research Center (KUTTAM) Rumeli Feneri, Sarıyer, Istanbul, Turkey
| | - Farhad Bani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Savas Tasoglu
- Koç University Translational Medicine Research Center (KUTTAM) Rumeli Feneri, Sarıyer, Istanbul, Turkey.,Faculty of Engineering, Mechanical Engineering Department, Koç University, Rumeli Feneri Yolu, Sarıyer, Istanbul, Turkey
| | - Amir Zarebkohan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Imam Reza St., Daneshgah St., 51666-14756, Tabriz, Iran.
| | - Emel Sokullu
- School of Medicine, Biophysics Department, Koç University, Rumeli Fener, Sarıyer, Istanbul, Turkey. .,Koç University Translational Medicine Research Center (KUTTAM) Rumeli Feneri, Sarıyer, Istanbul, Turkey.
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18
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Gentiluomo M, Canzian F, Nicolini A, Gemignani F, Landi S, Campa D. Germline genetic variability in pancreatic cancer risk and prognosis. Semin Cancer Biol 2020; 79:105-131. [DOI: 10.1016/j.semcancer.2020.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 02/07/2023]
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19
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Principe DR, Rana A. Updated risk factors to inform early pancreatic cancer screening and identify high risk patients. Cancer Lett 2020; 485:56-65. [PMID: 32389710 DOI: 10.1016/j.canlet.2020.04.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/06/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic adenocarcinoma (PDAC) is associated with poor clinical outcomes and incomplete responses to conventional therapy. Therefore, there is an unmet clinical need to better understand the predisposing factors for pancreatic cancer in hopes of providing early screening to high-risk patients. While select risk factors such as age, race, and family history, or predisposing syndromes are unavoidable, there are several new and established risk factors that allow for intervention, namely by counseling patients to make the appropriate lifestyle modifications. Here, we discuss the best-studied risk factors for PDAC such as tobacco use and chronic pancreatitis, as well as newly emerging risk factors including select nutritional deficits, bacterial infections, and psychosocial factors. As several of these risk factors appear to be additive or synergistic, by understanding their relationships and offering coordinated, multidisciplinary care to high-risk patients, it may be possible to reduce pancreatic cancer incidence and improve clinical outcomes through early detection.
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Affiliation(s)
- Daniel R Principe
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA; Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA.
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
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