Skip to main content
SpringerLink
Log in

Mitochondrial DNA Polymorphism and Risk of Cancer

  • Protocol
Cancer Epidemiology

Part of the book series: Methods in Molecular Biology ((MIMB,volume 471))

Summary

ATP (energy production) production is not the only function of the mitochondria. Mitochondria perform multiple cellular functions. Among others, these functions include control of cell death, growth, devel opment, integration of signals from mitochondria to nucleus and nucleus to mitochondria, and various metabolic pathways. Although defects in mitochondrial function are most commonly associated with bioenergetic deficiencies, our studies demonstrate that mitochondrial defects lead to genome instability in the nuclear DNA, resistance to apoptosis and induction of NADPH oxidase, a designated producer of reactive oxygen species. These transformations in cellular phenotype are known contributors to the development of tumors in humans. Consistent with the role of mitochondria in carcinogenesis, studies in the past few years have described an increased risk of cancers associated with specific mitochondrial DNA (mtDNA) polymorphism among various different haplogroups in human population. However, molecular mechanisms underlying increased risk of cancer due to specific mtDNA polymorphisms is currently lacking. It is likely that mtDNA polymorphisms in mitochondrial genes involved in electron transport chain and oxidative phosphorylation result in increased oxidative stress and hypermutagenesis of mitochondrial as well as nuclear DNA. We suggest that in studies relating to cancer epidemiology, the significance of a particular mtDNA polymorphism(s) should be analyzed together with other polymor phisms in mtDNA and in nuclear DNA.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Modica-Napolitano, J. S., and Singh, K. K. (2004) Mitochondrial dysfunction in cancer. Mitochondrion 4, 755–762.

    Article  CAS  PubMed  Google Scholar 

  2. Modica-Napolitano, J. S., and Singh, K. (2002) Mitochondria as targets for detec tion and treatment of cancer. Expert Rev Mol Med 4, 1–19.

    Article  PubMed  Google Scholar 

  3. Warburg, O. (1930) Metabolism of Tumors, Arnold Constable, London, UK.

    Google Scholar 

  4. Singh, K. K. (ed.) (1998) Mitochondrial DNA Mutations in Aging, Disease, and Cancer. Springer, New York.

    Google Scholar 

  5. Schatz, G. (1996) The protein import sys tem of mitochondria. J Biol Chem 271, 31763–31766.

    CAS  PubMed  Google Scholar 

  6. Grossman, L. I., and Shoubridge, E. A. (1996) Mitochondrial genetics and human disease. Bioessays 18, 983–991.

    Article  CAS  PubMed  Google Scholar 

  7. Johns, D. R. (1995) Seminars in medicine of the Beth Israel Hospital, Boston: mito-chondrial DNA and disease. N Engl J Med 333, 638–644.

    Article  CAS  PubMed  Google Scholar 

  8. Malhi, R. S., Mortensen, H. M., Eshleman, J. A., Kemp, B. M., Lorenz, J. G., Kaes-tle, F. A., Johnson, J. R., Gorodezky, C., and Smith, D. G. (2003) Native American mtDNA prehistory in the American South west. Am J Phys Anthropol 120(2), 108–24.

    Article  PubMed  Google Scholar 

  9. Desouki, M. M., Kulawiec, M., Bansal, S., Das, G. M., and Singh, K. K. (2005) Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors. Cancer Biol Ther 4, 1367– 1373.

    Article  CAS  PubMed  Google Scholar 

  10. Singh, K. K., Kulawiec, M., Still, I., Desouki, M. M., Geradts, J., and Matsui, S. (2005) Inter-genomic cross talk between mitochon dria and the nucleus plays an important role in tumorigenesis. Gene 354, 140–146.

    Article  CAS  PubMed  Google Scholar 

  11. Singh, K. K. (2004) Mitochondrial damage checkpoint in apoptosis and genome stabil ity. FEMS Yeast Res 2, 127–132.

    Article  CAS  Google Scholar 

  12. Rasmussen, A. K., Chatterjee, A., Rasmus sen, L. J., and Singh, K. K. (2003) Mitochon dria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae. Nucleic Acids Res 31, 3909–3917.

    Article  CAS  PubMed  Google Scholar 

  13. Delsite, R. L., Rasmussen, L. J., Rasmus sen, A. K., Kalen, A., Goswami, P. C., and Singh, K. K. (2003) Mitochondrial impair ment is accompanied by impaired oxidative DNA repair in the nucleus. Mutagenesis 18, 497–503.

    Article  CAS  PubMed  Google Scholar 

  14. Park, S. Y., Chang, I., Kim, J. Y., Kang, S. W., Park, S. H., Singh, K., and Lee, M. S. (2004) Resistance of mitochondrial DNA depleted cells against cell death: Role of mitochondrial superoxide dismutase. J Biol Chem 279, 7512–7520.

    Article  CAS  PubMed  Google Scholar 

  15. Verma, M., Naviaux, R. K., Tanaka, M., Kumar, D., Franceschi, C., and Singh, K. K. (2007) Mitochondrial DNA and cancer epidemiology. Cancer Res 67(2), 437–9.

    Article  CAS  PubMed  Google Scholar 

  16. Booker, L. M., Habermacher, G. M., Jes sie, B. C., Sun, Q. C., Baumann, A. K., Amin, M., Lim, S. D., Fernandez-Golarz, C., Lyles, R. H., Brown, M. D., Marshall, F. F., and Petros, J. A. (2006) North American white mitochondrial haplogroups in pros tate and renal cancer. J Urol 175, 468–472; discussion 472–463.

    Article  CAS  PubMed  Google Scholar 

  17. Canter, J. A., Kallianpur, A. R., Parl, F. F., and Millikan, R. C. (2005) Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 65, 8028–8033.

    CAS  PubMed  Google Scholar 

  18. Petros, J. A., Baumann, A. K., Ruiz-Pesini, E., Amin, M. B., Sun, C. Q., Hall, J, Lim, S., Issa, M. M., Flanders, W. D., Hosseini, S. H., Marshall, F. F., and Wallace, D. C. (2005) mtDNA mutations increase tumori-genicity in prostate cancer. Proc Natl Acad Sci USA 102, 719–724.

    Article  CAS  PubMed  Google Scholar 

  19. Darvishi, K., Sharma, S., Bhat, A. K., Rai, E., and Bamezai, R. N. (2007) Mitochon drial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer. Cancer Lett 249(2), 249–55.

    Article  CAS  PubMed  Google Scholar 

  20. Bai, R. K., Leal, S. M., Covarrubias, D., Liu, A., and Wong, L. J. (2007) Mitochondrial genetic background modifies breast cancer risk. Cancer Res 67(10), 4687–94.

    Article  CAS  PubMed  Google Scholar 

  21. Wang, L., Bamlet, W. R., de Andrade, M., Boardman, L. A., Cunningham, J. M., Thi bodeau, S. N., and Petersen, G. M. (2007) Mitochondrial genetic polymorphisms and pancreatic cancer risk. Cancer Epidemiol. Biomarkers Prev. 16(7), 1455–9.

    CAS  Google Scholar 

  22. Fuku, N., Park, K. S., Yamada, Y., Nishigaki, Y., Cho, Y. M., Matsuo, H., Segawa, T., Watanabe, S., Kato, K., Yokoi, K., Nozawa, Y., Lee, H. K., and Tanaka, M. (2007) Mito-chondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Am J Hum Genet 80(3), 407–15.

    Article  CAS  PubMed  Google Scholar 

  23. Alexe, G., Fuku, N., Bilal, E., Ueno, H., Nishigaki, Y., Fujita, Y., Ito, M., Arai, Y., Hirose, N., Bhanot, G., and Tanaka, M. (2007). Enrichment of longevity phenotype in mtDNA haplogroups D4b2b, D4a, and D5 in the Japanese population. Hum Genet 121(3–4), 347–56.

    Article  PubMed  Google Scholar 

  24. van der Walt, J.M., Nicodemus, K. K., Mar tin, E. R., Scott, W. K., Nance, M. A., Watts, R. L., Hubble, J. P., Haines, J. L., Koller, W. C., Lyons, K., Pahwa, R., Stern, M. B., Colcher, A., Hiner, B. C., Jankovic, J., Ondo, W. G., Allen, F. H., Jr., Goetz, C. G., Small, G. W., Mastaglia, F., Stajich, J. M., McLaurin, A.C., Middleton, L. T., Scott, B. L., Schmechel, D. E., Pericak-Vance, M. A., and Vance, J. M. (2003) Mitochondrial pol ymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 72(4), 804–811.

    Article  PubMed  Google Scholar 

  25. Lee, C. F., Liu, C. Y., Chen, S. M., Sikorska, M., Lin, C. Y., Chen, T. L., and Wei, Y. H. (2005) Mitochondrial genome instability and mtDNA depletion in human cancers. Ann NY Acad Sci 1042, 109–122.

    Article  CAS  PubMed  Google Scholar 

  26. Clayton, D. A., and Vinograd, J. (1967) Circular dimer and catenate forms of mito-chondrial DNA in human leukaemic leuco cytes. J Pers 35, 652–657.

    Google Scholar 

  27. Welter, C., Kovacs, G., Seitz, G., and Blin N. (1989) Alteration of mitochondrial DNA in human oncocytomas Genes Chromosome Cancer 1, 79–82.

    CAS  Google Scholar 

  28. Selvanayagam, P., and Rajaraman, S. (1996) Detection of mitochondrial genome deple tion by a novel cDNA in renal cell carci noma. Lab Invest 74, 592–599.

    CAS  PubMed  Google Scholar 

  29. Sangkhathat, S., Chiengkriwate, P., Kusafuka, T., Patrapinyokul, S., and Fukuzawa, M. (2005) Renal cell carcinoma in a pediat ric patient with an inherited mitochondrial mutation. Pediatr Surg Int 21, 745–748.

    Article  PubMed  Google Scholar 

  30. Jiang, W. W., Masayesva, B., Zahurak, M., Carvalho, A. L., Rosenbaum, E., Mambo, E., Zhou, S., Minhas, K., Benoit, N., Westra, W. H., Alberg, A., Sidransky, D., Koch, W., and Califano, J. (2005) Increased mitochondrial DNA content in saliva associ ated with head and neck cancer. Clin Cancer Res 11, 2486–2491.

    Article  CAS  PubMed  Google Scholar 

  31. Kim, M. M., Clinger, J. D., Masayesva, B. G., Ha, P. K., Zahurak, M. L., Westra, W. H., and Califano, J. A. (2004) Mitochondrial DNA quantity increases with histopatho logic grade in premalignant and malignant head and neck lesions. Clin Cancer Res 10, 8512–8515.

    Article  CAS  PubMed  Google Scholar 

  32. Mambo, E., Chatterjee, A., Xing, M., Tallini, G., Haugen, B. R., Yeung, S. C., Sukumar, S., and Sidransky, D. (2005) Tumor-specific changes in mtDNA content in human can cer. Int J Cancer 116, 920–924.

    Article  CAS  PubMed  Google Scholar 

  33. Wu, C. W., Yin, P. H., Hung, W. Y., Li, A. F., Li, S. H., Chi, C. W., Wei, Y. H. and Lee, C. (2005) Mitochondrial DNA muta tions and mitochondrial DNA depletion in gastric cancer. Genes Chromosomes Cancer 44, 19–28.

    Article  CAS  PubMed  Google Scholar 

  34. Wang, Y., Liu, V. W., Xue, W. C., Tsang, P. C., Cheung, A. N., and Ngan, H. Y. (2005) The increase of mitochondrial DNA con tent in endometrial adenocarcinoma cells: a quantitative study using laser-captured microdissected tissues. Gynecol Oncol 98, 104–110.

    Article  CAS  PubMed  Google Scholar 

  35. Tseng, L. M., Yin, P. H., Chi, C. W., Hsu, C. Y., Wu, C. W., Lee, L. M., Wei, Y. H., and Lee, H. C. (2006) Mitochondrial DNA mutations and mitochondrial DNA deple tion in breast cancer. Genes Chromosomes Cancer 45, 629–638.

    Article  CAS  PubMed  Google Scholar 

  36. Kulawiec, M., Arnouk, H., Desouki, M. M., Kazim, L., Still, I., Singh, K. K. (2006) Proteomic anlysis of proteins involved in mitochondria-to-nucleus retrograde response in human cancer cells. Cancer Biol Ther 8, 967–975.

    Google Scholar 

  37. Vignais, P. V. (2002) The superoxide-gen-erating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci 59, 1428–1459.

    Article  CAS  PubMed  Google Scholar 

  38. Lambeth, J. D. (2004) Oxygen. Nat Rev Immunol 4, 181–189.

    Article  CAS  PubMed  Google Scholar 

  39. Cheng, G., Cao, Z., Xu, X., van Meir, E. G., and Lambeth, J. D. (2001) Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269, 131–140.

    Article  CAS  PubMed  Google Scholar 

  40. Shidara, Y., Yamagata, K., Kanamori, T., Nakano, K., Kwong, J. Q., Manfredi, G., Oda, H., and Ohta, S. (2005) Positive con tribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res 65, 1655–1663.

    Article  CAS  PubMed  Google Scholar 

  41. Moreno-Loshuertos, R., Acin-Perez, R., Fernandez-Silva, P., Movilla, N., Perez-Martos, A., Rodriguez de Cordoba, S., Gal lardo, M. E., and Enriquez, J. A. (2007) Differences in reactive oxygen species pro duction explain the phenotypes Nat Genet 38, 1261–1268.

    Article  Google Scholar 

Download references

Acknowledgments

Studies in our laboratory were supported by National Institutes of Health grants R01 CA121904, 113655 and 116430 (to K.K.S.) and the New York State Department of Health (to M.K. and K.K.S.).

Author information

Authors and Affiliations

  1. Department of Cancer Genetics, Roswell Park Cancer Institute, NY, Buffalo, USA

    Keshav K. Singh & Mariola Kulawiec

Authors
  1. Keshav K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariola Kulawiec
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Cancer Control and Population Sciences Bethesda, Maryland, 20892, USA

    Mukesh Verma PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Singh, K.K., Kulawiec, M. (2009). Mitochondrial DNA Polymorphism and Risk of Cancer. In: Verma, M. (eds) Cancer Epidemiology. Methods in Molecular Biology, vol 471. Humana Press. https://doi.org/10.1007/978-1-59745-416-2_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-416-2_15

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-987-1

  • Online ISBN: 978-1-59745-416-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation