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A prospective study of mitochondrial DNA copy number and the risk of prostate cancer

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Abstract

Purpose

Evidence suggests that mitochondrial DNA (mtDNA) copy number increases in response to DNA damage. Increased mtDNA copy number has been observed in prostate cancer (PCa) cells, suggesting a role in PCa development, but this association has not yet been investigated prospectively.

Methods

We conducted a nested case–control study (793 cases and 790 controls) of men randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to evaluate the association between pre-diagnosis mtDNA copy number, measured in peripheral blood leukocytes, and the risk of PCa. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) and polytomous logistic regression to analyze differences in associations by non-aggressive (Stage I/II AND Gleason grade < 8) or aggressive (Stage III/IV OR Gleason grade ≥ 8) PCa.

Results

Although mtDNA copy number was not significantly associated with PCa risk overall (OR 1.23, 95% CI 0.97–1.55, p = 0.089), increasing mtDNA copy number was associated with an increased risk of non-aggressive PCa (OR 1.29, 95% CI 1.01–1.65, p = 0.044) compared to controls. No association was observed with aggressive PCa (OR 1.02, 95% CI 0.64–1.63, p = 0.933). Higher mtDNA copy number was also associated with increased PSA levels among controls (p = 0.014).

Conclusions

These results suggest that alterations in mtDNA copy number may reflect disruption of the normal prostate glandular architecture seen in early-stage disease, as opposed to reflecting the large number of tumor cells seen with advanced PCa.

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References

  1. Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125(7):1241–1252. doi:10.1016/j.cell.2006.06.010

    Article  CAS  PubMed  Google Scholar 

  2. Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J et al (2008) Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst 100(15):1104–1112. doi:10.1093/jnci/djn213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moraes CT (2001) What regulates mitochondrial DNA copy number in animal cells? Trends Genet TIG 17(4):199–205

    Article  CAS  PubMed  Google Scholar 

  4. Mengel-From J, Thinggaard M, Dalgard C, Kyvik KO, Christensen K, Christiansen L (2014) Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly. Hum Genet 133(9):1149–1159. doi:10.1007/s00439-014-1458-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Clayton DA (1984) Transcription of the mammalian mitochondrial genome. Annu Rev Biochem 53:573–594. doi:10.1146/annurev.bi.53.070184.003041

    Article  CAS  PubMed  Google Scholar 

  6. Mancini M, Anderson BO, Caldwell E, Sedghinasab M, Paty PB, Hockenbery DM (1997) Mitochondrial proliferation and paradoxical membrane depolarization during terminal differentiation and apoptosis in a human colon carcinoma cell line. J Cell Biol 138(2):449–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Masayesva BG, Mambo E, Taylor RJ, Goloubeva OG, Zhou S, Cohen Y et al (2006) Mitochondrial DNA content increase in response to cigarette smoking. Cancer Epidemiol Biomark Prev 15(1):19–24. doi:10.1158/1055-9965.EPI-05-0210

    Article  CAS  Google Scholar 

  8. Shen M, Zhang L, Bonner MR, Liu CS, Li G, Vermeulen R et al (2008) Association between mitochondrial DNA copy number, blood cell counts, and occupational benzene exposure. Environ Mol Mutagen 49(6):453–457. doi:10.1002/em.20402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lee HC, Yin PH, Lu CY, Chi CW, Wei YH (2000) Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem J 348 (Pt 2):425–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang J, Li D, Qu F, Chen Y, Li G, Jiang H, et al (2014) Association of leukocyte mitochondrial DNA content with glioma risk: evidence from a Chinese case-control study. BMC Cancer 14:680. doi:10.1186/1471-2407-14-680

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bonner MR, Shen M, Liu CS, Divita M, He X, Lan Q (2009) Mitochondrial DNA content and lung cancer risk in Xuan Wei, China. Lung Cancer 63(3):331–334. doi:10.1016/j.lungcan.2008.06.012

    Article  PubMed  Google Scholar 

  12. Shen J, Platek M, Mahasneh A, Ambrosone CB, Zhao H (2010) Mitochondrial copy number and risk of breast cancer: a pilot study. Mitochondrion 10(1):62–68. doi:10.1016/j.mito.2009.09.004

    Article  CAS  PubMed  Google Scholar 

  13. Hosgood HD 3rd, Liu CS, Rothman N, Weinstein SJ, Bonner MR, Shen M et al (2010) Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study. Carcinogenesis 31(5):847–849. doi:10.1093/carcin/bgq045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lan Q, Lim U, Liu CS, Weinstein SJ, Chanock S, Bonner MR et al (2008) A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma. Blood 112(10):4247–4249. doi:10.1182/blood-2008-05-157974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hofmann JN, Hosgood HD 3rd, Liu CS, Chow WH, Shuch B, Cheng WL et al (2014) A nested case-control study of leukocyte mitochondrial DNA copy number and renal cell carcinoma in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Carcinogenesis 35(5):1028–1031. doi:10.1093/carcin/bgt495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lynch SM, Weinstein SJ, Virtamo J, Lan Q, Liu CS, Cheng WL et al (2011) Mitochondrial DNA copy number and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention study. Cancer Prev Res 4(11):1912–1919. doi:10.1158/1940-6207.CAPR-11-0002

    Article  CAS  Google Scholar 

  17. Purdue MP, Hofmann JN, Colt JS, Hoxha M, Ruterbusch JJ, Davis FG et al (2012) A case-control study of peripheral blood mitochondrial DNA copy number and risk of renal cell carcinoma. PLoS ONE 7(8):e43149. doi:10.1371/journal.pone.0043149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xia P, An HX, Dang CX, Radpour R, Kohler C, Fokas E et al (2009) Decreased mitochondrial DNA content in blood samples of patients with stage I breast cancer. BMC Cancer 9:454. doi:10.1186/1471-2407-9-454

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yu M, Zhou Y, Shi Y, Ning L, Yang Y, Wei X et al (2007) Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life 59(7):450–457. doi:10.1080/15216540701509955

    Article  CAS  PubMed  Google Scholar 

  20. Xie H, Lev D, Gong Y, Wang S, Pollock RE, Wu X et al (2013) Reduced mitochondrial DNA copy number in peripheral blood leukocytes increases the risk of soft tissue sarcoma. Carcinogenesis 34(5):1039–1043. doi:10.1093/carcin/bgt023

    Article  CAS  PubMed  Google Scholar 

  21. Zhou W, Zhu M, Gui M, Huang L, Long Z, Wang L et al (2014) Peripheral blood mitochondrial DNA copy number is associated with prostate cancer risk and tumor burden. PLoS ONE 9(10):e109470. doi:10.1371/journal.pone.0109470

    Article  PubMed  PubMed Central  Google Scholar 

  22. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR et al (2012) Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 104(2):125–132. doi:10.1093/jnci/djr500

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hayes RB, Reding D, Kopp W, Subar AF, Bhat N, Rothman N et al (2000) Etiologic and early marker studies in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Controll Clin Trials 21(6 Suppl):349S–355S

    Article  CAS  Google Scholar 

  24. Berndt SI, Wang Z, Yeager M, Alavanja MC, Albanes D, Amundadottir L et al (2015) Two susceptibility loci identified for prostate cancer aggressiveness. Nat Commun 6:6889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Peyromaure M, Debre B, Mao K, Zhang G, Wang Y, Sun Z et al (2005) Management of prostate cancer in China: a multicenter report of 6 institutions. J Urol 174(5):1794–1797. doi:10.1097/01.ju.0000176817.46279.93

    Article  PubMed  Google Scholar 

  26. Williams MA, Sanchez SE, Ananth CV, Hevner K, Qiu C, Enquobahrie DA (2013) Maternal blood mitochondrial DNA copy number and placental abruption risk: results from a preliminary study. Int J Mol Epidemiol Genet 4(2):120–127

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee HK, Song JH, Shin CS, Park DJ, Park KS, Lee KU et al (1998) Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 42(3):161–167

    Article  CAS  PubMed  Google Scholar 

  28. Wang YC, Lee WC, Liao SC, Lee LC, Su YJ, Lee CT et al (2011) Mitochondrial DNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients. Journal of Nephrol 24(3):351–358. doi:10.5301/jn.2010.5816

    Article  CAS  Google Scholar 

  29. Allen JA, Coombs MM (1980) Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA. Nature 287(5779):244–245

    Article  CAS  PubMed  Google Scholar 

  30. Kim HY, Kim HR, Kang MG, Trang NT, Baek HJ, Moon JD et al (2014) Profiling of biomarkers for the exposure of polycyclic aromatic hydrocarbons: lamin-A/C isoform 3, poly[ADP-ribose] polymerase 1, and mitochondria copy number are identified as universal biomarkers. BioMed Res Int 2014:605135. doi:10.1155/2014/605135

    PubMed  PubMed Central  Google Scholar 

  31. Pavanello S, Dioni L, Hoxha M, Fedeli U, Mielzynska-Svach D, Baccarelli AA (2013) Mitochondrial DNA copy number and exposure to polycyclic aromatic hydrocarbons. Cancer Epidemiol Biomark Prev 22(10):1722–1729. doi:10.1158/1055-9965.epi-13-0118

    Article  CAS  Google Scholar 

  32. Carugno M, Pesatori AC, Dioni L, Hoxha M, Bollati V, Albetti B et al (2012) Increased mitochondrial DNA copy number in occupations associated with low-dose benzene exposure. Environ Health Perspect 120(2):210–215. doi:10.1289/ehp.1103979

    Article  CAS  PubMed  Google Scholar 

  33. Tan D, Goerlitz DS, Dumitrescu RG, Han D, Seillier-Moiseiwitsch F, Spernak SM et al (2008) Associations between cigarette smoking and mitochondrial DNA abnormalities in buccal cells. Carcinogenesis 29(6):1170–1177. doi:10.1093/carcin/bgn034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nelson WG, De Marzo AM, Isaacs WB (2003) Prostate cancer. N Engl J Med 349(4):366–381. doi:10.1056/NEJMra021562

    Article  CAS  PubMed  Google Scholar 

  35. Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, van Breemen R et al (2001) Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Cancer Inst 93(24):1872–1879

    Article  CAS  PubMed  Google Scholar 

  36. Lee W, Johnson J, Gough DJ, Donoghue J, Cagnone GL, Vaghjiani V et al (2015) Mitochondrial DNA copy number is regulated by DNA methylation and demethylation of POLGA in stem and cancer cells and their differentiated progeny. Cell Death Dis 6:e1664. doi:10.1038/cddis.2015.34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors’ contributions

AM performed the statistical analysis and drafted the manuscript. QL participated in the coordination of the study. JNH participated in the coordination of the study. CSL, WLC, and TTL performed the mitochondrial DNA assay. SIB conceived of the study, participated in its design and coordination, and helped draft the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Amy Moore, Qing Lan, Jonathan N. Hofmann & Sonja I. Berndt

  2. Vascular and Genomic Research Center, Changhua Christian Hospital, 7F No. 235, Syuguang Rd., Changhua, 500, Taiwan

    Chin-San Liu, Wen-Ling Cheng & Ta-Tsung Lin

Authors
  1. Amy Moore
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  2. Qing Lan
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  3. Jonathan N. Hofmann
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  4. Chin-San Liu
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  6. Ta-Tsung Lin
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  7. Sonja I. Berndt
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Corresponding author

Correspondence to Amy Moore.

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The authors have no conflict of interest to disclose.

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Moore, A., Lan, Q., Hofmann, J.N. et al. A prospective study of mitochondrial DNA copy number and the risk of prostate cancer. Cancer Causes Control 28, 529–538 (2017). https://doi.org/10.1007/s10552-017-0879-x

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  • DOI: https://doi.org/10.1007/s10552-017-0879-x

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