Mutations in the mitochondrial DNA D-loop region and breast cancer risk

  • Chuanzhong Ye
  • Xiao Ou Shu
  • Larry Pierce
  • Wanqing Wen
  • Regina Courtney
  • Yu-Tang Gao
  • Wei Zheng
  • Qiuyin Cai


Mitochondrial genome alterations have been suggested to play an important role in carcinogenesis. The D-loop region of mitochondrial DNA (mtDNA) contains essential transcription and replication elements, and mutations in this region may serve as a potential sensor for cellular DNA damage and a marker for cancer development. Using data and samples from the Shanghai Breast Cancer Study, we investigated MnlI restriction sites located between nucleotides 16,106 and 16,437 of the mtDNA D-loop region to evaluate restriction fragment length polymorphism (RFLP) patterns in tumor tissue from 501 primary breast cancer patients when compared with tumor tissue from 203 women with benign breast disease (BBD). RFLP patterns in correspondingly paired, adjacent, non-tumor tissues taken from 120 primary breast cancer patients and 59 BBD controls were also evaluated. Five common RFLP patterns were observed, and no significant differences were observed in the distribution of these patterns between tumor and adjacent non-tumor tissue samples from breast cancer patients and tissue samples from BBD controls. On the other hand, somatic MnlI site mutations, defined as a difference in MnlI RFLP pattern between tumor tissue and the corresponding, adjacent, non-tumor tissue, occurred more frequently in breast cancer patients (28.3%) than in BBD patients (15.3%) (P = 0.05) and more frequently in proliferative BBD (13.0%) than in non-proliferative BBD (7.1%). Our data suggest that somatic MnlI site mutations may play a role in the pathogenesis of breast cancer.


Mitochondrial DNA MnlI restriction site mutation Breast cancer risk 



Benign breast disease


Confidence interval


Displacement loop


Mitochondrial DNA


Mitochondrial single-stranded DNA-binding protein


Nucleotide position


Odds ratio


Reactive oxygen species



We thank Ms. Qing Wang for her excellent technical laboratory assistance and Ms. Bethanie Hull for technical assistance in manuscript preparation. This study would not have been possible without the support of all of the study participants and research staff of the Shanghai Breast Cancer Study. This research was supported by United States Department of Defense Breast Cancer Research Program grant DAMD17-02-1-0603 and National Cancer Institute grants R01 CA064277 and R01 CA90899.


  1. 1.
    Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147. doi: 10.1038/13779 CrossRefPubMedGoogle Scholar
  2. 2.
    Bianchi NO, Bianchi MS, Richard SM (2001) Mitochondrial genome instability in human cancers. Mutat Res 488:9–23. doi: 10.1016/S1383-5742(00)00063-6 CrossRefPubMedGoogle Scholar
  3. 3.
    Richard SM, Bailliet G, Paez GL, Bianchi MS, Peltomaki P, Bianchi NO (2000) Nuclear and mitochondrial genome instability in human breast cancer. Cancer Res 60:4231–4237PubMedGoogle Scholar
  4. 4.
    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 9:5636–5641PubMedGoogle Scholar
  5. 5.
    Lievre A, Chapusot C, Bouvier AM, Zinzindohoue F, Piard F, Roignot P, Arnould L, Beaune P, Faivre J, Laurent-Puig P (2005) Clinical value of mitochondrial mutations in colorectal cancer. J Clin Oncol 23:3517–3525. doi: 10.1200/JCO.2005.07.044 CrossRefPubMedGoogle Scholar
  6. 6.
    Gille JJ, Joenje H (1992) Cell culture models for oxidative stress: superoxide and hydrogen peroxide versus normobaric hyperoxia. Mutat Res 275:405–414PubMedGoogle Scholar
  7. 7.
    Tan DJ, Bai RK, Wong LJ (2002) Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer. Cancer Res 62:972–976PubMedGoogle Scholar
  8. 8.
    Zhu W, Qin W, Bradley P, Wessel A, Puckett CL, Sauter ER (2005) Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid. Carcinogenesis 26:145–152. doi: 10.1093/carcin/bgh282 CrossRefPubMedGoogle Scholar
  9. 9.
    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 Chromosom Cancer 45:629–638. doi: 10.1002/gcc.20326 CrossRefPubMedGoogle Scholar
  10. 10.
    Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B (1998) Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20:291–293. doi: 10.1038/3108 CrossRefPubMedGoogle Scholar
  11. 11.
    Gao YT, Shu XO, Dai Q, Potter JD, Brinton LA, Wen W, Sellers TA, Kushi LH, Ruan Z, Bostick RM, Jin F, Zheng W (2000) Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study. Int J Cancer 87:295–300. doi: 10.1002/1097-0215(20000715)87:2<295::AID-IJC23>3.0.CO;2-7 CrossRefPubMedGoogle Scholar
  12. 12.
    Schnitt SCJ (1999) Pathology of benign breast disorders. In: Harris JR (ed) Diseases of the breast. Lippincott Williams & Wilkins, Philadelphia, pp 75–93Google Scholar
  13. 13.
    Shu XO, Jin F, Dai Q, Shi JR, Potter JD, Brinton LA, Hebert JR, Ruan Z, Gao YT, Zheng W (2001) Association of body size and fat distribution with risk of breast cancer among Chinese women. Int J Cancer 94:449–455. doi: 10.1002/ijc.1487 CrossRefPubMedGoogle Scholar
  14. 14.
    Yasukawa T, Yang MY, Jacobs HT, Holt IJ (2005) A bidirectional origin of replication maps to the major noncoding region of human mitochondrial DNA. Mol Cell 18:651–662. doi: 10.1016/j.molcel.2005.05.002 CrossRefPubMedGoogle Scholar
  15. 15.
    Takamatsu C, Umeda S, Ohsato T, Ohno T, Abe Y, Fukuoh A, Shinagawa H, Hamasaki N, Kang D (2002) Regulation of mitochondrial D-loops by transcription factor A and single-stranded DNA-binding protein. EMBO Rep 3:451–456. doi: 10.1093/embo-reports/kvf099 CrossRefPubMedGoogle Scholar
  16. 16.
    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. doi: 10.1080/15216540701509955 CrossRefPubMedGoogle Scholar
  17. 17.
    Fish J, Raule N, Attardi G (2004) Discovery of a major D-loop replication origin reveals two modes of human mtDNA synthesis. Science 306:2098–2101. doi: 10.1126/science.1102077 CrossRefPubMedGoogle Scholar
  18. 18.
    Park KS, Chan JC, Chuang LM, Suzuki S, Araki E, Nanjo K, Ji L, Ng M, Nishi M, Furuta H, Shirotani T, Ahn BY, Chung SS, Min HK, Lee SW, Kim JH, Cho YM, Lee HK (2008) A mitochondrial DNA variant at position 16189 is associated with type 2 diabetes mellitus in Asians. Diabetologia 51:602–608. doi: 10.1007/s00125-008-0933-z CrossRefPubMedGoogle Scholar
  19. 19.
    Wen W, Ren Z, Shu XO, Cai Q, Ye C, Gao YT, Zheng W (2007) Expression of cytochrome P450 1B1 and catechol-O-methyltransferase in breast tissue and their associations with breast cancer risk. Cancer Epidemiol Biomarkers Prev 16:917–920. doi: 10.1158/1055-9965.EPI-06-1032 CrossRefPubMedGoogle Scholar
  20. 20.
    Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney SD, Pankratz VS, Hillman DW, Suman VJ, Johnson J, Blake C, Tlsty T, Vachon CM, Melton LJIII, Visscher DW (2005) Benign breast disease and the risk of breast cancer. N Engl J Med 353:229–237. doi: 10.1056/NEJMoa044383 CrossRefPubMedGoogle Scholar
  21. 21.
    Silvera SA, Rohan TE (2008) Benign proliferative epithelial disorders of the breast: a review of the epidemiologic evidence. Breast Cancer Res Treat 110:397–409. doi: 10.1007/s10549-007-9740-3 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Chuanzhong Ye
    • 1
  • Xiao Ou Shu
    • 1
  • Larry Pierce
    • 1
  • Wanqing Wen
    • 1
  • Regina Courtney
    • 1
  • Yu-Tang Gao
    • 2
  • Wei Zheng
    • 1
  • Qiuyin Cai
    • 1
  1. 1.Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer CenterVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of EpidemiologyShanghai Cancer InstituteShanghaiPeople’s Republic of China

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