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Sequence variations of mitochondrial DNA D-loop region are highly frequent events in familial breast cancer

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Journal of Biomedical Science

Abstract

Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations. The non-coding displacement (D)-loop, especially a mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310), has been recently identified as a frequent hotspot of mutations in human neoplasia, including breast cancer. To further explore the sequence variations of mitochondrial D-loop region in familial breast cancer and their possible associations with breast cancer risk, PCR-SSCP and direct DNA sequencing methods were used to detect the variants of the mtDNA D-Loop in 23 familial breast cancer patients as well as three high-risk cancer families. Compared to that in sporadic breast tumors (53.3%, 16/30) and healthy blood donors (6.7%, 2/30), we identified a total of 126 sequence alterations in 23/23 (100%) of familial breast cancer patients, including eight novel nucleotide variants. Among these changes, A to G at nt.263, T to C at nt.489, T to C at nt.310, TC insertion at nt.311, CA deletion at nt.522, and C to G at nt.527 were highly frequent ones. In addition, among three high-risk cancer families, we found that individuals affected with breast cancer harbored more mtDNA sequence variants in mtDNA D310 area than other affected family members. Together, our data indicate that sequence variants within the mtDNA D-Loop region are frequent events in Chinese familial breast cancer patients. Some of these nucleotide abnormalities, particularly those in D310 segment, might be involved in the breast carcinogenesis and could be included in a panel of molecular biomarkers for cancer susceptibility early-detection strategy.

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References

  1. Bray F, McCarron P, Parkin DM (2004) The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res 6:229–239

    Article  PubMed  Google Scholar 

  2. Antoniou AC, Easton DF (2006) Models of genetic susceptibility to breast cancer. Oncogene 25:5898–5905

    Article  PubMed  CAS  Google Scholar 

  3. Eng C, Hampel H, de la Chapelle A (2001) Genetic testing for cancer predisposition. Annu Rev Med 52:371–400

    Article  PubMed  CAS  Google Scholar 

  4. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, Foretova L, Soucek P, King MC (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379–1388

    Article  PubMed  CAS  Google Scholar 

  5. Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11:103–105

    Article  PubMed  CAS  Google Scholar 

  6. Zhi X, Szabo C, Chopin S, Suter N, Wang QS, Ostrander EA, Sinilnikova OM, Lenoir GM, Goldgar D, Shi YR (2002) BRCA1 and BRCA2 sequence variants in Chinese breast cancer families. Hum Mutat 20:474

    Article  PubMed  Google Scholar 

  7. Song CG, Hu Z, Yuan WT, Di GH, Shen ZZ, Huang W, Shao ZM (2006) BRCA1 and BRCA2 gene mutations of familial breast cancer from Shanghai in China. Chin J Med Genet 23:27–31

    CAS  Google Scholar 

  8. Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36

    Article  PubMed  CAS  Google Scholar 

  9. Chen XJ, Butow RA (2005) The organization and inheritance of the mitochondrial genome. Nat Rev Genet 6:815–825

    Article  PubMed  CAS  Google Scholar 

  10. Clayton DA (2003) Mitochondrial DNA replication: what we know. IUBMB Life 55:213–217

    Article  PubMed  CAS  Google Scholar 

  11. Lee HC, Yin PH, Lin JC, Wu CC, Chen CY, Wu CW, Chi CW, Tam TN, Wei YH (2005) Mitochondrial genome instability and mtDNA depletion in human cancers. Ann N Y Acad Sci 1042:109–122

    Article  PubMed  CAS  Google Scholar 

  12. Chatterjee A, Mambo E, Sidransky D (2006) Mitochondrial DNA mutations in human cancer. Oncogene 25:4663–4674

    Article  PubMed  CAS  Google Scholar 

  13. Lee HC, Hsu LS, Yin PH, Lee LM, Chi CW (2007) Heteroplasmic mutation of mitochondrial DNA D-loop and 4977-bp deletion in human cancer cells during mitochondrial DNA depletion. Mitochondrion 7:157–163

    Article  PubMed  CAS  Google Scholar 

  14. Tamori A, Nishiguchi S, Nishikawa M, Kubo S, Koh N, Hirohashi K, Shiomi S, Inoue M (2004) Correlation between clinical characteristics and mitochondrial D-loop DNA mutations in hepatocellular carcinoma. J Gastroenterol 39:1063–1068

    Article  PubMed  CAS  Google Scholar 

  15. Lee HC, Li SH, Lin JC, Wu CC, Yeh DC, Wei YH (2004) Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma. Mutat Res 547:71–78

    PubMed  CAS  Google Scholar 

  16. Van Trappen PO, Cullup T, Troke R, Swann D, Shepherd JH, Jacobs IJ, Gayther SA, Mein CA (2007) Somatic mitochondrial DNA mutations in primary and metastatic ovarian cancer. Gynecol Oncol 104:129–133

    Article  PubMed  CAS  Google Scholar 

  17. Liu VW, Shi HH, Cheung AN, Chiu PM, Leung TW, Nagley P, Wong LC, Ngan HY (2001) High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res 61:5998–6001

    PubMed  CAS  Google Scholar 

  18. Gomez-Zaera M, Abril J, Gonzalez L, Aguilo F, Condom E, Nadal M, Nunes V (2006) Identification of somatic and germline mitochondrial DNA sequence variants in prostate cancer patients. Mutat Res 595:42–51

    PubMed  CAS  Google Scholar 

  19. Maximo V, Soares P, Seruca R, Rocha AS, Castro P, Sobrinho-Simoes M (2001) Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma. Genes Chromosomes Cancer 32:136–143

    Article  PubMed  CAS  Google Scholar 

  20. Wu CW, Yin PH, Hung WY, Li AF, Li SH, Chi CW, Wei YH, Lee HC (2005) Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer. Genes Chromosomes Cancer 44:19–28

    Article  PubMed  CAS  Google Scholar 

  21. Lievre A, Blons H, Houllier AM, Laccourreye O, Brasnu D, Beaune P, Laurent-Puig P (2006) Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma. Br J Cancer 94:692–697

    PubMed  CAS  Google Scholar 

  22. Suzuki M, Toyooka S, Miyajima K, Iizasa T, Fujisawa T, Bekele NB, Gazdar AF (2003) Alterations in the mitochondrial displacement loop in lung cancers. Clin Cancer Res 9:5636–5641

    PubMed  CAS  Google Scholar 

  23. Tong BC, Ha PK, Dhir K, **ng M, Westra WH, Sidransky D, Califano JA (2003) Mitochondrial DNA alterations in thyroid cancer. J Surg Oncol 82:170–173

    Article  PubMed  CAS  Google Scholar 

  24. Parrella P, Seripa D, Matera MG, Rabitti C, Rinaldi M, Mazzarelli P, Gravina C, Gallucci M, Altomare V, Flammia G, Casalino B, Benedetti-Panici PL, Fazio VM (2003) Mutations of the D310 mitochondrial mononucleotide repeat in primary tumors and cytological specimens. Cancer Lett 190:73–77

    Article  PubMed  CAS  Google Scholar 

  25. Rosson D, Keshgegian AA (2004) Frequent mutations in the mitochondrial control region DNA in breast tissue. Cancer Lett 215:89–94

    Article  PubMed  CAS  Google Scholar 

  26. Schwartz S Jr, Alazzouzi H, Perucho M (2006) Mutational dynamics in human tumors confirm the neutral intrinsic instability of the mitochondrial D-loop poly-cytidine repeat. Genes Chromosomes Cancer 45:770–780

    Article  PubMed  CAS  Google Scholar 

  27. Yu M, Shi Y, Wei X, Yang Y, Zhou Y, Hao X, Zhang N, Niu R (2007) Depletion of mitochondrial DNA by ethidium bromide treatment inhibits the proliferation and tumorigenesis of T47D human breast cancer cells. Toxicol Lett 170:83–93

    Article  PubMed  CAS  Google Scholar 

  28. Yu M, Zhou Y, Shi Y, Ning L, Yang Y, Wei X, Zhang N, Hao X, Niu R (2007) Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life 59:450–457

    Article  PubMed  CAS  Google Scholar 

  29. Tseng LM, Yin PH, Chi CW, Hsu CY, Wu CW, Lee LM, Wei YH, Lee HC (2006) Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer. Genes Chromosomes Cancer 45:629–638

    Article  PubMed  CAS  Google Scholar 

  30. Mambo E, Chatterjee A, **ng M, Tallini G, Haugen BR, Yeung SC, Sukumar S, Sidransky D (2005) Tumor-specific changes in mtDNA content in human cancer. Int J Cancer 116:920–924

    Article  PubMed  CAS  Google Scholar 

  31. Bai RK, Leal SM, Covarrubias D, Liu A, Wong LJ (2007) Mitochondrial genetic background modifies breast cancer risk. Cancer Res 67:4687–4694

    Article  PubMed  CAS  Google Scholar 

  32. Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, Redston M, Cotterchio M, Knight J, Gryfe R, Gallinger S (2004) Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 96:1631–1634

    Article  PubMed  CAS  Google Scholar 

  33. Evans DG, Lalloo F (2002) Risk assessment and management of high risk familial breast cancer. J Med Genet 39:865–871

    Article  PubMed  CAS  Google Scholar 

  34. Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A (2001) Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 93:1215–1223

    Article  PubMed  CAS  Google Scholar 

  35. Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG (2003) Genetic associations in large versus small studies: an empirical assessment. Lancet 361:567–571

    Article  PubMed  Google Scholar 

  36. Wang Y, Michikawa Y, Mallidis C, Bai Y, Woodhouse L, Yarasheski KE, Miller CA, Askanas V, Engel WK, Bhasin S, Attardi G (2007) Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc Natl Acad Sci USA 98:4022–4027

    Article  Google Scholar 

  37. Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1996) Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286:774–779

    Article  Google Scholar 

  38. Darvishi K, Sharma S, Bhat AK, Rai E, Bamezai RN (2007) Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer. Cancer Lett 249:249–255

    Article  PubMed  CAS  Google Scholar 

  39. Wang L, Bamlet WR, de Andrade M, Boardman LA, Cunningham JM, Thibodeau SN, Petersen GM (2007) Mitochondrial genetic polymorphisms and pancreatic cancer risk. Cancer Epidemiol Biomarkers Prev 16:1455–1459

    Article  PubMed  CAS  Google Scholar 

  40. Lee HC, Wei YH (2005) Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol 37:822–834

    Article  PubMed  CAS  Google Scholar 

  41. Marcelino LA, Thilly WG (1999) Mitochondrial mutagenesis in human cells and tissues. Mutat Res 434:177–203

    PubMed  CAS  Google Scholar 

  42. Jackson AL, Loeb LA (2001) The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res 477:7–21

    PubMed  CAS  Google Scholar 

  43. Achanta G, Sasaki R, Feng L, Carew JS, Lu W, Pelicano H, Keating MJ, Huang P (2005) Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol gamma. EMBO J 24:3482–3492

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We sincerely thank the families for participating in this study and many clinicians who were willing to corporate. We are grateful to Dr. Marc Ekker, University of Ottawa, for critical reading and helpful comments on the manuscript. This work is supported by a research grant (No. 020217) from Tian** Municipal Science and Technology Commission, Tian**, P.R. China.

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Authors and Affiliations

  1. State Key Laboratory of Breast Cancer Prevention and Treatment, Cancer Hospital and Institute, Tian** Medical University, Tian**, 300060, P.R. China

    Man Yu, Yurong Shi, Fei Zhang, Yunli Zhou, Yi Yang, **yin Wei, Lin Zhang & Ruifang Niu

  2. Center for Advanced Research in Environmental Genomics (CAREG), University of Ottawa, 20 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5

    Man Yu

  3. Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada, K1H 8M5

    Man Yu

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  1. Man Yu
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Correspondence to Ruifang Niu.

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Yu, M., Shi, Y., Zhang, F. et al. Sequence variations of mitochondrial DNA D-loop region are highly frequent events in familial breast cancer. J Biomed Sci 15, 535–543 (2008). https://doi.org/10.1007/s11373-007-9229-4

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  • DOI: https://doi.org/10.1007/s11373-007-9229-4

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