Skip to main content
Top
Published in: Diagnostic Pathology 1/2014

Open Access 01-12-2014 | Research

Low copy number of mitochondrial DNA (mtDNA) predicts worse prognosis in early-stage laryngeal cancer patients

Authors: Siwen Dang, Yiping Qu, Jing Wei, Yuan Shao, Qi Yang, Meiju Ji, Bingyin Shi, Peng Hou

Published in: Diagnostic Pathology | Issue 1/2014

Login to get access

Abstract

Objectives

Alterations in mitochondrial DNA (mtDNA) copy number have been widely reported in various human cancers, and been considered to be an important hallmark of cancers. However, little is known about the value of copy number variations of mtDNA in the prognostic evaluation of laryngeal cancer.

Design and methods

Using real-time quantitative PCR method, we investigated mtDNA copy number in a cohort of laryngeal cancers (n =204) and normal laryngeal tissues (n =40), and explored the association of variable mtDNA copy number with clinical outcomes of laryngeal cancer patients.

Results

Our data showed that the relative mean mtDNA content was higher in the laryngeal cancer patients (11.91 ± 4.35 copies) than the control subjects (4.72 ± 0.70 copies). Moreover, we found that mtDNA content was negatively associated with cigarette smoking (pack-years), tumor invasion, and TNM stage. Notably, variable mtDNA content did not affect overall survival of laryngeal cancer patients. However, when the patients were categorized into early-stage and late-stage tumor groups according to TNM stage, we found that low mtDNA content was strongly associated with poor survival in the former, but not in the latter.

Conclusions

The present study demonstrated that low mtDNA content was strongly correlated with some of clinicopathological characteristics, such as cigarette smoking, tumor invasion and TNM stage. In addition, we found a strong link between low mtDNA content and worse survival of the patients with early-stage tumors. Taken together, low copy number of mtDNA may be a useful poor prognostic factor for early-stage laryngeal cancer patients.

Virtual slides

Appendix
Available only for authorised users
Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.PubMedCrossRef Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.PubMedCrossRef
2.
go back to reference Choong N, Vokes E: Expanding role of the medical oncologist in the management of head and neck cancer. CA Cancer J Clin. 2008, 58: 32-53. 10.3322/CA.2007.0004.PubMedCrossRef Choong N, Vokes E: Expanding role of the medical oncologist in the management of head and neck cancer. CA Cancer J Clin. 2008, 58: 32-53. 10.3322/CA.2007.0004.PubMedCrossRef
3.
go back to reference Almadori G, Bussu F, Paludettii G: Predictive factors of neck metastases in laryngeal squamous cell carcinoma. Towards an integrated clinico-molecular classification. Acta Otorhinolaryngol Ital. 2006, 26: 326-334.PubMedPubMedCentral Almadori G, Bussu F, Paludettii G: Predictive factors of neck metastases in laryngeal squamous cell carcinoma. Towards an integrated clinico-molecular classification. Acta Otorhinolaryngol Ital. 2006, 26: 326-334.PubMedPubMedCentral
4.
go back to reference Gourin CG, Conger BT, Sheils WC, Bilodeau PA, Coleman TA, Porubsky ES: The effect of treatment on survival in patients with advanced laryngeal carcinoma. Laryngoscope. 2009, 119: 1312-1317. 10.1002/lary.20477.PubMedCrossRef Gourin CG, Conger BT, Sheils WC, Bilodeau PA, Coleman TA, Porubsky ES: The effect of treatment on survival in patients with advanced laryngeal carcinoma. Laryngoscope. 2009, 119: 1312-1317. 10.1002/lary.20477.PubMedCrossRef
5.
go back to reference Johansen LV, Grau C, Overgaard J: Laryngeal carcinoma–multivariate analysis of prognostic factors in 1252 consecutive patients treated with primary radiotherapy. Acta Oncol. 2003, 42: 771-778. 10.1080/02841860310017595.PubMedCrossRef Johansen LV, Grau C, Overgaard J: Laryngeal carcinoma–multivariate analysis of prognostic factors in 1252 consecutive patients treated with primary radiotherapy. Acta Oncol. 2003, 42: 771-778. 10.1080/02841860310017595.PubMedCrossRef
6.
go back to reference Lohynska R, Slavicek A, Bahanan A, Novakova P: Predictors of local failure in early laryngeal cancer. Neoplasma. 2005, 52: 483-488.PubMed Lohynska R, Slavicek A, Bahanan A, Novakova P: Predictors of local failure in early laryngeal cancer. Neoplasma. 2005, 52: 483-488.PubMed
7.
go back to reference Marioni G, Marchese-Ragona R, Cartei G, Marchese F, Staffieri A: Current opinion in diagnosis and treatment of laryngeal carcinoma. Cancer Treat Rev. 2006, 32: 504-515. 10.1016/j.ctrv.2006.07.002.PubMedCrossRef Marioni G, Marchese-Ragona R, Cartei G, Marchese F, Staffieri A: Current opinion in diagnosis and treatment of laryngeal carcinoma. Cancer Treat Rev. 2006, 32: 504-515. 10.1016/j.ctrv.2006.07.002.PubMedCrossRef
8.
go back to reference Nguyen-Tan PF, Le QT, Quivey JM, Singer M, Terris DJ, Goffinet DR, Fu KK: Treatment results and prognostic factors of advanced T3–4 laryngeal carcinoma: the University of California, San Francisco (UCSF) and Stanford University Hospital (SUH) experience. Int J Radiat Oncol Biol Phys. 2001, 50: 1172-1180. 10.1016/S0360-3016(01)01538-3.PubMedCrossRef Nguyen-Tan PF, Le QT, Quivey JM, Singer M, Terris DJ, Goffinet DR, Fu KK: Treatment results and prognostic factors of advanced T3–4 laryngeal carcinoma: the University of California, San Francisco (UCSF) and Stanford University Hospital (SUH) experience. Int J Radiat Oncol Biol Phys. 2001, 50: 1172-1180. 10.1016/S0360-3016(01)01538-3.PubMedCrossRef
9.
go back to reference Yu L, Xiao-li D, Cheng T, Hong-gang L: Human telomerase RNA component (hTERC) gene amplification detected by FISH in precancerous lesions and carcinoma of the larynx. Diagn Pathol. 2002, 7: 34- Yu L, Xiao-li D, Cheng T, Hong-gang L: Human telomerase RNA component (hTERC) gene amplification detected by FISH in precancerous lesions and carcinoma of the larynx. Diagn Pathol. 2002, 7: 34-
10.
go back to reference Yurdanur S, Seda G, Sinan A, Filiz K, Bedri K: Poor prognostic clinicopathologic features correlate with VEGF expression but not with PTEN expression in squamous cell carcinoma of the larynx. Diagn Pathol. 2010, 5: 35-10.1186/1746-1596-5-35.CrossRef Yurdanur S, Seda G, Sinan A, Filiz K, Bedri K: Poor prognostic clinicopathologic features correlate with VEGF expression but not with PTEN expression in squamous cell carcinoma of the larynx. Diagn Pathol. 2010, 5: 35-10.1186/1746-1596-5-35.CrossRef
11.
go back to reference Hans-Ullrich V, Matthias S, Sylvia H, Philipp S, Rudolf H, Hans M-H, Matthias E: Differential diagnosis of laryngeal spindle cell carcinoma and inflammatory myofibroblastic tumor ? report of two cases with similar morphology. Diagn Pathol. 2007, 2: 1-10.1186/1746-1596-2-1.CrossRef Hans-Ullrich V, Matthias S, Sylvia H, Philipp S, Rudolf H, Hans M-H, Matthias E: Differential diagnosis of laryngeal spindle cell carcinoma and inflammatory myofibroblastic tumor ? report of two cases with similar morphology. Diagn Pathol. 2007, 2: 1-10.1186/1746-1596-2-1.CrossRef
12.
go back to reference Jiang WW, Masayesva B, Zahurak M, Carvalho AL, Rosenbaum E, Mambo E, Zhou S, Minhas K, Benoit N, Westra WH, Alberg A, Sidransky D, Koch W, Califano J: Increased mitochondrial DNA content in saliva associated with head and neck cancer. Clin Cancer Res. 2005, 11: 2486-2491. 10.1158/1078-0432.CCR-04-2147.PubMedCrossRef Jiang WW, Masayesva B, Zahurak M, Carvalho AL, Rosenbaum E, Mambo E, Zhou S, Minhas K, Benoit N, Westra WH, Alberg A, Sidransky D, Koch W, Califano J: Increased mitochondrial DNA content in saliva associated with head and neck cancer. Clin Cancer Res. 2005, 11: 2486-2491. 10.1158/1078-0432.CCR-04-2147.PubMedCrossRef
13.
go back to reference Jiang WW, Rosenbaum E, Mambo E, Zahurak M, Masayesva B, Carvalho AL, Zhou S, Westra WH, Alberg AJ, Sidransky D, Koch W, Califano JA: Decreased mitochondrial DNA content in posttreatment salivary rinses from head and neck cancer patients. Clin Cancer Res. 2006, 12: 1564-1569. 10.1158/1078-0432.CCR-05-1471.PubMedCrossRef Jiang WW, Rosenbaum E, Mambo E, Zahurak M, Masayesva B, Carvalho AL, Zhou S, Westra WH, Alberg AJ, Sidransky D, Koch W, Califano JA: Decreased mitochondrial DNA content in posttreatment salivary rinses from head and neck cancer patients. Clin Cancer Res. 2006, 12: 1564-1569. 10.1158/1078-0432.CCR-05-1471.PubMedCrossRef
14.
go back to reference Hatefi Y: The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem. 1985, 54: 1015-1069. 10.1146/annurev.bi.54.070185.005055.PubMedCrossRef Hatefi Y: The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem. 1985, 54: 1015-1069. 10.1146/annurev.bi.54.070185.005055.PubMedCrossRef
15.
go back to reference Fernández-Silva P, Enriquez JA, Montoya J: Replication and transcription of mammalian mitochondrial DNA. Exp Physiol. 2003, 88: 41-56. 10.1113/eph8802514.PubMedCrossRef Fernández-Silva P, Enriquez JA, Montoya J: Replication and transcription of mammalian mitochondrial DNA. Exp Physiol. 2003, 88: 41-56. 10.1113/eph8802514.PubMedCrossRef
16.
go back to reference Shadel GS: Expression and maintenance of mitochondrial DNA: new insights into human disease pathology. Am J Pathol. 2008, 172: 1445-1456. 10.2353/ajpath.2008.071163.PubMedPubMedCentralCrossRef Shadel GS: Expression and maintenance of mitochondrial DNA: new insights into human disease pathology. Am J Pathol. 2008, 172: 1445-1456. 10.2353/ajpath.2008.071163.PubMedPubMedCentralCrossRef
18.
go back to reference Gredilla R, Bohr VA, Stevnsner T: Mitochondrial DNA repair and association with aging–an update. Exp Gerontol. 2010, 45: 478-488. 10.1016/j.exger.2010.01.017.PubMedPubMedCentralCrossRef Gredilla R, Bohr VA, Stevnsner T: Mitochondrial DNA repair and association with aging–an update. Exp Gerontol. 2010, 45: 478-488. 10.1016/j.exger.2010.01.017.PubMedPubMedCentralCrossRef
19.
go back to reference Guo W, Yang D, Xu H, Zhang Y, Huang J, Yang Z, Chen X, Huang Z: Mutations in the D-loop region and increased copy number of mitochondrial DNA in human laryngeal squamous cell carcinoma. Mol Biol Rep. 2013, 40: 13-20. 10.1007/s11033-012-1939-7.PubMedCrossRef Guo W, Yang D, Xu H, Zhang Y, Huang J, Yang Z, Chen X, Huang Z: Mutations in the D-loop region and increased copy number of mitochondrial DNA in human laryngeal squamous cell carcinoma. Mol Biol Rep. 2013, 40: 13-20. 10.1007/s11033-012-1939-7.PubMedCrossRef
20.
go back to reference Shi J, Zhang G, Yao D, Liu W, Wang N, Ji M, He N, Shi B, Hou P: Prognostic significance of aberrant gene methylation in gastric cancer. Am J Cancer Res. 2012, 2: 116-129.PubMedPubMedCentral Shi J, Zhang G, Yao D, Liu W, Wang N, Ji M, He N, Shi B, Hou P: Prognostic significance of aberrant gene methylation in gastric cancer. Am J Cancer Res. 2012, 2: 116-129.PubMedPubMedCentral
21.
go back to reference Zhang G, Qu Y, Dang S, Yang Q, Shi B, Hou P: Variable copy number of mitochondrial DNA (mtDNA) predicts worse prognosis in advanced gastric cancer patients. Diagn Pathol. 2013, 8: 173-10.1186/1746-1596-8-173.PubMedPubMedCentralCrossRef Zhang G, Qu Y, Dang S, Yang Q, Shi B, Hou P: Variable copy number of mitochondrial DNA (mtDNA) predicts worse prognosis in advanced gastric cancer patients. Diagn Pathol. 2013, 8: 173-10.1186/1746-1596-8-173.PubMedPubMedCentralCrossRef
22.
go back to reference Shi J, Yao D, Liu W, Wang N, Lv H, Zhang G, Ji M, Xu L, He N, Shi B, Hou P: Highly frequent PIK3CA amplification is associated with poor prognosis in gastric cancer. BMC Cancer. 2012, 12: 50-10.1186/1471-2407-12-50.PubMedPubMedCentralCrossRef Shi J, Yao D, Liu W, Wang N, Lv H, Zhang G, Ji M, Xu L, He N, Shi B, Hou P: Highly frequent PIK3CA amplification is associated with poor prognosis in gastric cancer. BMC Cancer. 2012, 12: 50-10.1186/1471-2407-12-50.PubMedPubMedCentralCrossRef
23.
go back to reference Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J, Amos C, Shields PG, Benowitz NL, Gu J, De Andrade M, Swan GE, Wu X: Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst. 2008, 100: 1104-1112. 10.1093/jnci/djn213.PubMedPubMedCentralCrossRef Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J, Amos C, Shields PG, Benowitz NL, Gu J, De Andrade M, Swan GE, Wu X: Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst. 2008, 100: 1104-1112. 10.1093/jnci/djn213.PubMedPubMedCentralCrossRef
24.
go back to reference Liao LM, Baccarelli A, Shu XO, Gao YT, Ji BT, Yang G, Li HL, Hoxha M, Dioni L, Rothman N, Zheng W, Chow WH: Mitochondrial DNA copy number and risk of gastric cancer: a report from the Shanghai Women’s Health Study. Cancer Epidemiol Biomarkers Prev. 2011, 20: 1944-1949. 10.1158/1055-9965.EPI-11-0379.PubMedPubMedCentralCrossRef Liao LM, Baccarelli A, Shu XO, Gao YT, Ji BT, Yang G, Li HL, Hoxha M, Dioni L, Rothman N, Zheng W, Chow WH: Mitochondrial DNA copy number and risk of gastric cancer: a report from the Shanghai Women’s Health Study. Cancer Epidemiol Biomarkers Prev. 2011, 20: 1944-1949. 10.1158/1055-9965.EPI-11-0379.PubMedPubMedCentralCrossRef
25.
go back to reference Wallace DC: A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005, 39: 359-407. 10.1146/annurev.genet.39.110304.095751.PubMedPubMedCentralCrossRef Wallace DC: A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005, 39: 359-407. 10.1146/annurev.genet.39.110304.095751.PubMedPubMedCentralCrossRef
27.
go back to reference Clay Montier LL, Deng JJ, Bai Y: Number matters: control of mammalian mitochondrial DNA copy number. J Genet Genomics. 2009, 36: 125-131. 10.1016/S1673-8527(08)60099-5.PubMedCrossRef Clay Montier LL, Deng JJ, Bai Y: Number matters: control of mammalian mitochondrial DNA copy number. J Genet Genomics. 2009, 36: 125-131. 10.1016/S1673-8527(08)60099-5.PubMedCrossRef
28.
go back to reference Copeland WC, Wachsman JT, Johnson FM, Penta JS: Mitochondrial DNA alterations in cancer. Cancer Invest. 2002, 20: 557-569. 10.1081/CNV-120002155.PubMedCrossRef Copeland WC, Wachsman JT, Johnson FM, Penta JS: Mitochondrial DNA alterations in cancer. Cancer Invest. 2002, 20: 557-569. 10.1081/CNV-120002155.PubMedCrossRef
29.
go back to reference Verschoor ML, Wilson LA, Singh G: Mechanisms associated with mitochondrial-generated reactive oxygen species in cancer. Can J Physiol Pharmacol. 2010, 88: 204-219. 10.1139/Y09-135.PubMedCrossRef Verschoor ML, Wilson LA, Singh G: Mechanisms associated with mitochondrial-generated reactive oxygen species in cancer. Can J Physiol Pharmacol. 2010, 88: 204-219. 10.1139/Y09-135.PubMedCrossRef
30.
go back to reference Verschoor ML, Ungard R, Harbottle A, Jakupciak JP, Parr RL, Singh G: Mitochondria and cancer: past, present, and future. Biomed Res Int. 2013, 2013: 612369-PubMedPubMedCentralCrossRef Verschoor ML, Ungard R, Harbottle A, Jakupciak JP, Parr RL, Singh G: Mitochondria and cancer: past, present, and future. Biomed Res Int. 2013, 2013: 612369-PubMedPubMedCentralCrossRef
31.
go back to reference Kroemer G: Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun. 2003, 304: 433-435. 10.1016/S0006-291X(03)00614-4.PubMedCrossRef Kroemer G: Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun. 2003, 304: 433-435. 10.1016/S0006-291X(03)00614-4.PubMedCrossRef
32.
go back to reference Zheng S, Qian P, Li F, Qian G, Wang C, Wu G, Li Q, Chen Y, Li J, Li H, He B, Ji F: Association of mitochondrial DNA variations with lung cancer risk in a Han Chinese population from southwestern China. PLoS One. 2012, 7: e31322-10.1371/journal.pone.0031322.PubMedPubMedCentralCrossRef Zheng S, Qian P, Li F, Qian G, Wang C, Wu G, Li Q, Chen Y, Li J, Li H, He B, Ji F: Association of mitochondrial DNA variations with lung cancer risk in a Han Chinese population from southwestern China. PLoS One. 2012, 7: e31322-10.1371/journal.pone.0031322.PubMedPubMedCentralCrossRef
33.
go back to reference Masuda S, Kadowaki T, Kumaki N, Tang X, Tokuda Y, Yoshimura S, Takekoshi S, Osamura RY: Analysis of gene alterations of mitochondrial DNA D-loop regions to determine breast cancer clonality. Br J Cancer. 2012, 107: 2016-2023. 10.1038/bjc.2012.505.PubMedPubMedCentralCrossRef Masuda S, Kadowaki T, Kumaki N, Tang X, Tokuda Y, Yoshimura S, Takekoshi S, Osamura RY: Analysis of gene alterations of mitochondrial DNA D-loop regions to determine breast cancer clonality. Br J Cancer. 2012, 107: 2016-2023. 10.1038/bjc.2012.505.PubMedPubMedCentralCrossRef
34.
go back to reference Xu E, Sun W, Gu J, Chow WH, Ajani JA, Wu X: Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma. Carcinogenesis. 2013, 34: 2521-2524. 10.1093/carcin/bgt230.PubMedPubMedCentralCrossRef Xu E, Sun W, Gu J, Chow WH, Ajani JA, Wu X: Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma. Carcinogenesis. 2013, 34: 2521-2524. 10.1093/carcin/bgt230.PubMedPubMedCentralCrossRef
35.
go back to reference Warowicka A, Kwasniewska A, Gozdzicka-Jozefiak A: Alterations in mtDNA: a qualitative and quantitative study associated with cervical cancer development. Gynecol Oncol. 2013, 129: 193-198. 10.1016/j.ygyno.2013.01.001.PubMedCrossRef Warowicka A, Kwasniewska A, Gozdzicka-Jozefiak A: Alterations in mtDNA: a qualitative and quantitative study associated with cervical cancer development. Gynecol Oncol. 2013, 129: 193-198. 10.1016/j.ygyno.2013.01.001.PubMedCrossRef
36.
go back to reference Lee HC, Lu CY, Fahn HJ, Wei YH: Aging- and smoking-associated alteration in the relative content of mitochondrial DNA in human lung. FEBS Lett. 1998, 441: 292-296. 10.1016/S0014-5793(98)01564-6.PubMedCrossRef Lee HC, Lu CY, Fahn HJ, Wei YH: Aging- and smoking-associated alteration in the relative content of mitochondrial DNA in human lung. FEBS Lett. 1998, 441: 292-296. 10.1016/S0014-5793(98)01564-6.PubMedCrossRef
37.
go back to reference Mondal R, Ghosh SK, Choudhury JH, Seram A, Sinha K, Hussain M, Laskar RS, Rabha B, Dey P, Ganguli S, Nathchoudhury M, Talukdar FR, Chaudhuri B, Dhar B: Mitochondrial DNA copy number and risk of oral cancer: a report from Northeast India. PLoS One. 2013, 8: e57771-10.1371/journal.pone.0057771.PubMedPubMedCentralCrossRef Mondal R, Ghosh SK, Choudhury JH, Seram A, Sinha K, Hussain M, Laskar RS, Rabha B, Dey P, Ganguli S, Nathchoudhury M, Talukdar FR, Chaudhuri B, Dhar B: Mitochondrial DNA copy number and risk of oral cancer: a report from Northeast India. PLoS One. 2013, 8: e57771-10.1371/journal.pone.0057771.PubMedPubMedCentralCrossRef
38.
go back to reference Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, Belcheva A, Bucana CD, Semenza GL, Ellis LM: Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst. 2004, 96: 946-956. 10.1093/jnci/djh168.PubMedCrossRef Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, Belcheva A, Bucana CD, Semenza GL, Ellis LM: Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst. 2004, 96: 946-956. 10.1093/jnci/djh168.PubMedCrossRef
Metadata
Title
Low copy number of mitochondrial DNA (mtDNA) predicts worse prognosis in early-stage laryngeal cancer patients
Authors
Siwen Dang
Yiping Qu
Jing Wei
Yuan Shao
Qi Yang
Meiju Ji
Bingyin Shi
Peng Hou
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2014
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/1746-1596-9-28

Other articles of this Issue 1/2014

Diagnostic Pathology 1/2014 Go to the issue