Mitochondrial DNA variant interactions modify breast cancer risk


Interactions between mitochondrial deoxyribonucleic acid (mtDNA) variants and the risk of developing breast cancer were investigated using DNA samples collected from non-Jewish European American breast cancer patients and ethnically age-matched female controls. Logistic regression was used to evaluate two-way interactions between 17 mtDNA variants. To control for multiple testing, empirical P values were calculated using permutation. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to measure the contribution of variants in modifying the risk of developing breast cancer. A highly significant interaction was identified between variants 12308G and 10398G (empirical P value = 0.0028), with results suggesting these variants increase the risk of a woman developing breast cancer (OR = 3.03; 95% CI 1.53–6.11). Nominal significant P values were also observed for interactions between mtDNA variants 709A and 16189C; 4216C and 10398G; 4216C and 16189C; 10398G and 16159C; 13368A and 16189C; and 14766T and 16519C. However, after adjusting for multiple testing, the P values did not remain significant. Although it is important to elucidate the main effect of mtDNA variants on the risk of developing breast cancer, understanding gene × gene interactions will give a greater knowledge of disease etiology and aid in interpreting a woman’s risk of developing breast cancer.

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

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

  3. Canter JA, Kallianpur AR, Parl FF, Millikan RC (2005) Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 65:8028–8033

  4. Carrieri G, Bonafe M, De Luca M, Rose G, Varcasia O, Bruni A, Maletta R, Nacmias B, Sorbi S, Corsonello F, Feraco E, Andreev KF, Yashin AI, Franceschi C, De Benedictis G (2001) Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer’s disease. Hum Genet 108:194–198

  5. 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

  6. Filosto M, Tomelleri G, Tonin P, Scarpelli M, Vattemi G, Rizzuto N, Padovani A, Simonati A (2007) Neuropathology of mitochondrial diseases. Biosci Rep 27:23–30

  7. Finsterer J (2007) Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol Scand 116:1–14

  8. Forli F, Passetti S, Mancuso M, Seccia V, Siciliano G, Nesti C, Berrettini S (2007) Mitochondrial syndromic sensorineural hearing loss. Biosci Rep 27:113–123

  9. Kokotas H, Petersen MB, Willems PJ (2007) Mitochondrial deafness. Clin Genet 71:379–391

  10. Levy-Lahad E, Friedman E (2007) Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer 96:11–15

  11. Mims MP, Hayes TG, Zheng S, Leal SM, Frolov A, Ittmann MM, Wheeler TM, Prchal JT (2006) Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 66:1880; author reply 1880–1881

  12. Mortiboys HJ, Schaefer J, Reichmann H, Jackson S (2007) Mitochondrial dysfunction in Parkinson’s disease–revisited. Neurol Neurochir Pol 41:150–159

  13. Mosquera-Miguel A, Alvarez-Iglesias V, Carracedo A, Salas A, Vega A, Milne R, de Leon AC, Benitez J (2008) Is mitochondrial DNA variation associated with sporadic breast cancer risk? Cancer Res 68:623–625 author reply 624

  14. Onyango IG (2008) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Neurochem Res 33:589–597

  15. Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102:719–724

  16. Setiawan VW, Chu LH, John EM, Ding YC, Ingles SA, Bernstein L, Press MF, Ursin G, Haiman CA, Neuhausen SL (2008) Mitochondrial DNA G10398A variant is not associated with breast cancer in African-American women. Cancer Genet Cytogenet 181:16–19

  17. Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC (1996) Classification of European mtDNAs from an analysis of three European populations. Genetics 144:1835–1850

  18. Verma M, Naviaux RK, Tanaka M, Kumar D, Franceschi C, Singh KK (2007) Meeting report: mitochondrial DNA and cancer epidemiology. Cancer Res 67:437–439

  19. Wong LJ (2007) Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve 36:279–293

  20. Yen MY, Wang AG, Wei YH (2006) Leber’s hereditary optic neuropathy: a multifactorial disease. Prog Retin Eye Res 25:381–396

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This study was supported in part by NIH grant CA10023 and Department of Defense US Army Breast Cancer Research Program, DAMD17-01-1-0258.

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Correspondence to Suzanne M. Leal.

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D. Covarrubias and R.-K. Bai contributed equally to this article.

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Covarrubias, D., Bai, R., Wong, L.C. et al. Mitochondrial DNA variant interactions modify breast cancer risk. J Hum Genet 53, 924–928 (2008) doi:10.1007/s10038-008-0331-x

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  • Mitochondrial DNA
  • Breast cancer
  • Interaction

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