Mitochondria are essential intracellular organelles that are responsible for energy
metabolism, cell growth, and differentiation, redox homeostasis, oncogenic signaling,
and apoptosis. These multifunctional organelles have been implicated in cancer initiation,
progression, and metastasis, relapse, and acquired drug resistance due to metabolic
alterations in transformed cells. Maternally inherited mitochondrial DNA (mtDNA) is
thought to contribute to cancer development and prognosis and proposed as a therapeutic
target for cancer treatment. In this review, we summarize the current knowledge of
mtDNA alterations, with a specific focus on somatic changes, germline variants, haplogroups,
large deletions, and mtDNA content changes associated with cancer susceptibility and
prognosis. We also discuss the potential of mtDNA as biomarkers of cancer detection
and targets of cancer treatment. Deeper understanding of the mechanisms underlying
these associations requires further investigation.
Abbreviations:
mtDNA (mitochondrial DNA), ROS (reactive oxygen species), D-loop (displacement-loop), COI (cytochrome c oxidase subunit I), CSB1 (conserved sequence block 1), NADH (nicotinamide adenine dinucleotide hydrogen), ND (NADH dehydrogenase), mtDNMT1 (mtDNA methyltransferase), TNM (The TNM Classification of Malignant Tumours), SNV (single nucleotide variant), ATP (adenosine triphosphate), PCR (polymerase chain reaction.)To read this article in full you will need to make a payment
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References
- With chartbook on long-term trends in health.Health, United States, Hyattsville (MD)2016/2017
- On the origin of cancer cells.Science. 1956; 123: 309-314
- Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674
- On respiratory impairment in cancer cells.Science. 1956; 124: 267-269
- Mitochondria and Cancer.Cell. 2016; 166: 555-566
- Mitochondria and cancer.Mol Cell. 2016; 61: 667-676
- Mitochondria and cancer.Nat Rev Cancer. 2012; 12: 685-698
- The human mitochondrial transcriptome.Cell. 2011; 146: 645-658
- The mitochondrial genome: structure, transcription, translation and replication.Biochim Biophys Acta. 1999; 1410: 103-123
- Human mitochondrial DNA.J Mol Biol. 1968; 36: 419-423
- The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease.Nat Rev Genet. 2015; 16: 530-542
- High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection.Nat Genet. 2001; 28: 147-150
- Heteroplasmic mitochondrial DNA mutations in normal and tumour cells.Nature. 2010; 464: 610-614
- The cancer genome.Nature. 2009; 458: 719-724
- A comprehensive catalogue of somatic mutations from a human cancer genome.Nature. 2010; 463: 191-196
- Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells.J Biol Chem. 1997; 272: 25409-25412
- mtDNA mutations increase tumorigenicity in prostate cancer.Proc Natl Acad Sci USA. 2005; 102: 719-724
- Mitochondrial mutations in early stage prostate cancer and bodily fluids.Oncogene. 2001; 20: 5195-5198
- Somatic mutations throughout the entire mitochondrial genome are associated with elevated PSA levels in prostate cancer patients.Am J Human Genet. 2010; 87: 802-812
- Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.Elife. 2014; 3eLife.02935
- Simultaneous DNA and RNA mapping of somatic mitochondrial mutations across diverse human cancers.PLoS Genet. 2015; 11e1005333
- Somatic mutations of the mitochondrial genome in human colorectal tumours.Nat Genet. 1998; 20: 291-293
- Mitochondrial genome variation and prostate cancer: a review of the mutational landscape and application to clinical management.Oncotarget. 2017; 8: 71342-71357
- The mitochondrial and autosomal mutation landscapes of prostate cancer.Eur Urol. 2013; 63: 702-708
- Mitochondrial mutations drive prostate cancer aggression.Nat Commun. 2017; 8: 656
- Mutational load of the mitochondrial genome predicts pathological features and biochemical recurrence in prostate cancer.Aging (Albany NY). 2016; 8: 2702-2712
- Spectrum of mitochondrial genomic variation and associated clinical presentation of prostate cancer in South African men.Prostate. 2016; 76: 349-358
- Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer.Cancer Res. 2002; 62: 972-976
- Mutational patterns in the breast cancer mitochondrial genome, with clinical correlates.Carcinogenesis. 2014; 35: 1046-1054
- Somatic mutations of the mitochondrial genome in human breast cancers.Genes Chromosomes Cancer. 2011; 50: 800-811
- Erythrocytosis in hepatocellular carcinoma portends poor prognosis by respiratory dysfunction secondary to mitochondrial DNA mutations.Hepatology. 2017; 65: 134-151
- Mitochondrial DNA depletion, mitochondrial mutations and high TFAM expression in hepatocellular carcinoma.Oncotarget. 2017; 8: 84373-84383
- Somatic mutations of mitochondrial genome in hepatocellular carcinoma.Mitochondrion. 2010; 10: 174-182
- Molecular alterations in mitochondrial DNA of hepatocellular carcinomas: is there a correlation with clinicopathological profile?.J Med Genet. 2004; 41: e65
- Prevalence of somatic mitochondrial mutations and spatial distribution of mitochondria in non-small cell lung cancer.Br J Cancer. 2017; 117: 220-226
- Detection of mitochondrial DNA mutations in nonmuscle invasive bladder cancer.Genet Test Mol Biomarkers. 2012; 16: 672-678
- Somatic mitochondrial DNA mutations in human chromophobe renal cell carcinomas.Genes Chromosomes Cancer. 2002; 35: 256-260
- Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers.Mod Pathol. 2014; 27: 1412-1420
- Somatic mitochondrial DNA mutations in primary and metastatic ovarian cancer.Gynecol Oncol. 2007; 104: 129-133
- Mitochondrial DNA alterations in thyroid cancer.J Surg Oncol. 2003; 82: 170-173
- Recurrent tissue-specific mtDNA mutations are common in humans.PLoS Genet. 2013; 9e1003929
- No association between the mitochondrial genome and prostate cancer risk: the multiethnic cohort.Cancer Epidemiol Biomarkers Prev. 2016; 25: 1001-1003
- Sequence variation in the mitochondrial gene cytochrome c oxidase subunit I and prostate cancer in African American men.Prostate. 2009; 69: 956-960
- Mitochondrial DNA sequence variation and risk of pancreatic cancer.Cancer Res. 2012; 72: 686-695
- Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women.Cancer Res. 2006; 66 (author reply -1): 1880
- Associations of mitochondrial polymorphisms with sporadic colorectal adenoma.Mol Carcinog. 2018; 57: 598-605
- Analysis of BRCA1 and mtDNA haplotypes and mtDNA polymorphism in familial breast cancer.Mitochondrial DNA. 2015; 26: 227-231
- Association of mitochondrial DNA displacement loop (CA)n dinucleotide repeat polymorphism with breast cancer risk and survival among Chinese women.Cancer Epidemiol Biomarkers Prev. 2008; 17: 2117-2122
- Association of mitochondrial DNA 10398 polymorphism in invasive breast cancer in Malay population of peninsular Malaysia.Malays J Med Sci. 2012; 19: 36-42
- Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland.Breast Cancer Res Treat. 2010; 121: 511-518
- Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer.Cancer Lett. 2007; 249: 249-255
- Genetic variations of mitochondrial genome modify risk and prognosis of hepatocellular carcinoma patients.Clin Res Hepatol Gastroenterol. 2017; 41: 378-385
- Associations between sequence variations in the mitochondrial DNA D-loop region and outcome of hepatocellular carcinoma.Oncol Lett. 2016; 11: 3723-3728
- Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.Am J Hum Genet. 2003; 72: 804-811
- Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics.PLoS Genet. 2006; 2: e128
- Mitochondrial DNA-dependent effects of valproate on mitochondrial calcium levels in transmitochondrial cybrids.Int J Neuropsychopharmacol. 2008; 11: 71-78
- Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women.Cancer Res. 2005; 65: 8028-8033
- Classification of European mtDNAs from an analysis of three European populations.Genetics. 1996; 144: 1835-1850
- Mitochondrial DNA diversity in the African American population.Mitochondrial DNA. 2015; 26: 445-451
- Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: implications for population susceptibility to diseases.Biochim Biophys Acta. 2014; 1842: 208-219
- Mitochondrial haplogroups H and J: risk and protective factors for ischemic cardiomyopathy.PloS one. 2012; 7: e44128
- Breast cancer-associated mitochondrial DNA haplogroup promotes neoplastic growth via ROS-mediated AKT activation.Int J Cancer. 2017; 142: 1786-1796
- North American white mitochondrial haplogroups in prostate and renal cancer.J Urol. 2006; 175 (discussion 72-3): 468-472
- Mitochondrial genetic background modifies breast cancer risk.Cancer Res. 2007; 67: 4687-4694
- Cancer type-specific modulation of mitochondrial haplogroups in breast, colorectal and thyroid cancer.BMC Cancer. 2010; 10: 421
- Mitochondrial variations in non-small cell lung cancer (NSCLC) survival.Cancer Inf. 2015; 14: 1-9
- Association of mitochondrial DNA variations with lung cancer risk in a Han Chinese population from southwestern China.PloS One. 2012; 7: e31322
- Association of mitochondrial haplogroup D and risk of esophageal cancer in Taihang Mountain and Chaoshan areas in China.Mitochondrion. 2011; 11: 27-32
- mtDNA evidence: genetic background associated with related populations at high risk for esophageal cancer between Chaoshan and Taihang Mountain areas in China.Genomics. 2007; 90: 474-481
- Mitochondrial polymorphisms as risk factors for endometrial cancer in southwest China.Int J Gynecol Cancer. 2006; 16: 1661-1667
- Breast cancer risk and genetic ancestry: a case-control study in Uruguay.BMC Womens Health. 2015; 15: 11
- Mitochondrial genotype and breast cancer predisposition.Oncol Rep. 2010; 24: 1521-1534
- Mitochondrial DNA haplogroup K as a contributor to protection against thyroid cancer in a population from southeast Europe.Mitochondrion. 2018; 39: 43-50
- Evaluating mitochondrial DNA in patients with breast cancer and benign breast disease.J Cancer Res Clin Oncol. 2011; 137: 669-675
- Increased risk of oral cancer in relation to common Indian mitochondrial polymorphisms and Autosomal GSTP1 locus.Cancer. 2007; 110: 1991-1999
- A comprehensive characterization of mitochondrial genome in papillary thyroid cancer.Int J Mol Sci. 2016; 17pii:E1594
- Mitochondrial DNA haplogroup N is associated good outcome of gastric cancer.Tumour Biol. 2014; 35: 12555-12559
- Identification of sequence polymorphisms in the mitochondrial displacement loop as risk factors for sporadic and familial breast cancer.Tumour Biol. 2014; 35: 4773-4777
- Association of genes, pathways, and haplogroups of the mitochondrial genome with the risk of colorectal cancer: the multiethnic cohort.PloS One. 2015; 10e0136796
- Mitochondrial DNA repair and aging.Mutat Res. 2002; 509: 127-151
- Mitochondrial common deletion, a potential biomarker for cancer occurrence, is selected against in cancer background: a meta-analysis of 38 studies.PloS One. 2013; 8: e67953
- Mitochondrial genome deletion aids in the identification of false- and true-negative prostate needle core biopsy specimens.Am J Clin Pathol. 2008; 129: 57-66
- Evaluation of two mitochondrial DNA biomarkers for prostate cancer detection.Cancer Biomark. 2015; 15: 763-773
- Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay.Prostate Cancer Prostatic Dis. 2010; 13: 126-131
- Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma.J Natl Cancer Inst. 2008; 100: 1104-1112
- Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers.Life Sci. 2011; 89: 65-71
- The mitochondrial DNA 4,977-bp deletion and its implication in copy number alteration in colorectal cancer.BMC Med Genet. 2011; 12: 8
- The increase of mitochondrial DNA content in endometrial adenocarcinoma cells: a quantitative study using laser-captured microdissected tissues.Gynecol Oncol. 2005; 98: 104-110
- The role of mitochondrial DNA alterations in esophageal squamous cell carcinomas.J Thorac Cardiovasc Surg. 2010; 139 (189–97 e4)
- Increased copy number of mitochondrial DNA predicts poor prognosis of esophageal squamous cell carcinoma.Oncol Lett. 2018; 15: 1014-1020
- Mitochondrial DNA content in paired normal and cancerous breast tissue samples from patients with breast cancer.J Cancer Res Clin Oncol. 2009; 135: 983-989
- Mitochondrial DNA content varies with pathological characteristics of breast cancer.J Oncol. 2011; 2011496189
- Aggressive triple negative breast cancers have unique molecular signature on the basis of mitochondrial genetic and functional defects.Biochim Biophys Acta. 2018; 1864: 1060-1071
- Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer.Prostate. 2018; 78: 25-31
- Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma.Mutat Res. 2004; 547: 71-78
- Mitochondrial DNA copy number variation across human cancers.Elife. 2016; 5
- Mitochondrial DNA quantity increases with histopathologic grade in premalignant and malignant head and neck lesions.Clin Cancer Res. 2004; 10: 8512-8515
- Association of decreased mitochondrial DNA content with ovarian cancer progression.Br J Cancer. 2006; 95: 1087-1091
- Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer.Genes Chromosomes Cancer. 2006; 45: 629-638
- Correlation between copy number of mitochondrial DNA and clinico-pathologic parameters of hepatocellular carcinoma.Eur J Surg Oncol. 2006; 32: 303-307
- Genetic determinants of mitochondrial content.Hum Mol Genet. 2007; 16: 1504-1514
- Mitochondrial DNA copy number is regulated by cellular proliferation: a role for Ras and p66(Shc).Biochim Biophys Acta. 2006; 1757: 624-630
- Decreased copy number of mitochondrial DNA in Ewing's sarcoma.Clin Chim Acta. 2010; 411: 679-683
- Mitochondrial DNA copy number in peripheral blood leukocytes and the aggressiveness of localized prostate cancer.Oncotarget. 2015; 6: 41988-41996
- Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer in African American men.PloS One. 2013; 8: e74688
- Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma.Carcinogenesis. 2002; 23: 759-768
- Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer.Genes Chromosomes Cancer. 2005; 44: 19-28
- High copy number of mitochondrial DNA predicts poor prognosis in patients with advanced stage colon cancer.Int J Biol Markers. 2016; 31 (e382–e8)
- An association analysis between mitochondrial DNA content, G10398A polymorphism, HPV infection, and the prognosis of cervical cancer in the Chinese Han population.Tumour Biol. 2016; 37: 5599-5607
- High copy number of mitochondrial DNA (mtDNA) predicts good prognosis in glioma patients.Am J Cancer Res. 2015; 5: 1207-1216
- Organization and dynamics of human mitochondrial DNA.J Cell Sci. 2004; 117: 2653-2662
- A single mitochondrial DNA deletion accurately detects significant prostate cancer in men in the PSA 'grey zone'.World J Urol. 2018; 36: 341-348
- Mitochondrial common deletion is elevated in blood of breast cancer patients mediated by oxidative stress.Mitochondrion. 2016; 26: 104-112
- Cell-free circulating mitochondrial DNA content and risk of hepatocellular carcinoma in patients with chronic HBV infection.Sci Rep. 2016; 6: 23992
- Mitochondrial copy number and risk of breast cancer: a pilot study.Mitochondrion. 2010; 10: 62-68
- Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors.Mol Cancer. 2009; 8: 105
- Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study.Carcinogenesis. 2010; 31: 847-849
- Circulating mitochondrial DNA level, a noninvasive biomarker for the early detection of gastric cancer.Cancer Epidemiol Biomarkers Prev. 2014; 23: 2430-2438
- A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma.Blood. 2008; 112: 4247-4249
- Association between mitochondrial DNA content in leukocytes and colorectal cancer risk: a case-control analysis.Cancer. 2011; 117: 3148-3155
- Cancer epigenomics: DNA methylomes and histone-modification maps.Nat Rev Genet. 2007; 8: 286-298
- Pervasive CpG suppression in animal mitochondrial genomes.Proc Natl Acad Sci USA. 1994; 91: 3799-3803
- Comparative analysis of human mitochondrial methylomes shows distinct patterns of epigenetic regulation in mitochondria.Mitochondrion. 2014; 18: 58-62
- DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria.Proc Natl Acad Sci USA. 2011; 108: 3630-3635
- Methylation of mitochondrial DNA is not a useful marker for cancer detection.Clin Chem. 2004; 50: 1480-1481
- Mitochondrial dysfunction and cancer metastasis.J Bioenerg Biomembr. 2012; 44: 619-622
- ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis.Science. 2008; 320: 661-664
- Mitochondrial ROS and cancer drug resistance: implications for therapy.Pharmacol Res. 2015; 100: 170-174
- Gefitinib-mediated reactive oxygen specie (ROS) instigates mitochondrial dysfunction and drug resistance in lung cancer cells.J Biol Chem. 2015; 290: 9101-9110
- Mitochondrial DNA mutation in serous ovarian cancer: implications for mitochondria-coded genes in chemoresistance.J Clin Oncol. 2012; 30: e373-e378
- Mitochondrial DNA depletion reduces PARP-1 levels and promotes progression of the neoplastic phenotype in prostate carcinoma.Cell Oncol. 2008; 30: 307-322
- Platinum-induced mitochondrial DNA mutations confer lower sensitivity to paclitaxel by impairing tubulin cytoskeletal organization.Hum Mol Genet. 2017; 26: 2961-2974
- The origin and diversification of mitochondria.Curr Biol. 2017; 27 (R1177–R92)
Article info
Publication history
Published online: June 25, 2018
Accepted:
June 19,
2018
Received in revised form:
June 18,
2018
Received:
April 4,
2018
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
