Association between mitochondrial genetic variation and breast cancer risk: The Multiethnic Cohort

English version

Autoři: Yuqing Li ^aff001; Elena E. Giorgi ^aff002; Kenneth B. Beckman ^aff003; Christian Caberto ^aff004; Remi Kazma ^aff005; Annette Lum-Jones ^aff004; Christopher A. Haiman ^aff006; Loïc Le Marchand ^aff004; Daniel O. Stram ^aff006; Richa Saxena ^aff007; Iona Cheng ^aff001
Působiště autorů: Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California, United States of America ^aff001; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico ^aff002; University of Minnesota Genomics Center, Minneapolis, Minnesota, United States of America ^aff003; Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America ^aff004; Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Switzerland ^aff005; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ^aff006; Center for Human Genetic Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America ^aff007; Program of Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America ^aff008
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0222284

Souhrn

Background

The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species.

Methods

To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study.

Results

We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk.

Conclusions

In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.

Klíčová slova:

Europe – Haplogroups – Mitochondria – Mitochondrial DNA – Breast cancer – Transfer RNA – African American people – Mitochondrial genetics

Zdroje

1. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society. 2019.

2. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343(2):78–85. Epub 2000/07/13. doi: 10.1056/NEJM200007133430201 10891514.

3. Fachal L, Dunning AM. From candidate gene studies to GWAS and post-GWAS analyses in breast cancer. Curr Opin Genet Dev. 2015;30:32–41. Epub 2015/03/03. S0959-437X(15)00005-2 [pii] doi: 10.1016/j.gde.2015.01.004 25727315.

4. Swerdlow AJ, De Stavola BL, Swanwick MA, Maconochie NE. Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet. 1997;350(9093):1723–8. Epub 1997/12/31. S0140673697055268 [pii]. doi: 10.1016/s0140-6736(97)05526-8 9413462.

5. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):D1001–6. Epub 2013/12/10. gkt1229 [pii] doi: 10.1093/nar/gkt1229 24316577; PubMed Central PMCID: PMC3965119.

6. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087–93. Epub 2007/05/29. nature05887 [pii] doi: 10.1038/nature05887 17529967; PubMed Central PMCID: PMC2714974.

7. Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39(7):870–4. Epub 2007/05/29. ng2075 [pii] doi: 10.1038/ng2075 17529973; PubMed Central PMCID: PMC3493132.

8. Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet. 2007;39(7):865–9. Epub 2007/05/29. ng2064 [pii] doi: 10.1038/ng2064 17529974.

9. Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber J, et al. Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A. 2008;105(11):4340–5. Epub 2008/03/11. 0800441105 [pii] doi: 10.1073/pnas.0800441105 18326623; PubMed Central PMCID: PMC2393811.

10. Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet. 2010;42(6):504–7. Epub 2010/05/11. ng.586 [pii] doi: 10.1038/ng.586 20453838; PubMed Central PMCID: PMC3632836.

11. Cai Q, Long J, Lu W, Qu S, Wen W, Kang D, et al. Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium. Hum Mol Genet. 2011;20(24):4991–9. Epub 2011/09/13. ddr405 [pii] doi: 10.1093/hmg/ddr405 21908515; PubMed Central PMCID: PMC3221542.

12. Fletcher O, Johnson N, Orr N, Hosking FJ, Gibson LJ, Walker K, et al. Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst. 2011;103(5):425–35. Epub 2011/01/26. djq563 [pii] doi: 10.1093/jnci/djq563 21263130.

13. Kim HC, Lee JY, Sung H, Choi JY, Park SK, Lee KM, et al. A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. Breast Cancer Res. 2012;14(2):R56. Epub 2012/03/29. bcr3158 [pii] doi: 10.1186/bcr3158 22452962; PubMed Central PMCID: PMC3446390.

14. Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, et al. Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer. PLoS Genet. 2012;8(2):e1002532. Epub 2012/03/03. doi: 10.1371/journal.pgen.1002532 PGENETICS-D-11-01537 [pii]. 22383897; PubMed Central PMCID: PMC3285588.

15. Siddiq A, Couch FJ, Chen GK, Lindstrom S, Eccles D, Millikan RC, et al. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Hum Mol Genet. 2012;21(24):5373–84. Epub 2012/09/15. dds381 [pii] doi: 10.1093/hmg/dds381 22976474; PubMed Central PMCID: PMC3510753.

16. Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet. 2013;45(4):392–8, 8e1-2. Epub 2013/03/29. ng.2561 [pii] doi: 10.1038/ng.2561 23535733; PubMed Central PMCID: PMC3771695.

17. Low SK, Takahashi A, Ashikawa K, Inazawa J, Miki Y, Kubo M, et al. Genome-wide association study of breast cancer in the Japanese population. PLoS One. 2013;8(10):e76463. Epub 2013/10/22. doi: 10.1371/journal.pone.0076463 PONE-D-13-29227 [pii]. 24143190; PubMed Central PMCID: PMC3797071.

18. Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45(4):353–61, 61e1-2. Epub 2013/03/29. ng.2563 [pii] doi: 10.1038/ng.2563 23535729; PubMed Central PMCID: PMC3771688.

19. Ahsan H, Halpern J, Kibriya MG, Pierce BL, Tong L, Gamazon E, et al. A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age. Cancer Epidemiol Biomarkers Prev. 2014;23(4):658–69. Epub 2014/02/05. 1055-9965.EPI-13-0340 [pii] doi: 10.1158/1055-9965.EPI-13-0340 24493630; PubMed Central PMCID: PMC3990360.

20. Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, et al. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat Genet. 2014;46(8):886–90. Epub 2014/07/21. ng.3041 [pii] doi: 10.1038/ng.3041 25038754; PubMed Central PMCID: PMC4127632.

21. Fejerman L, Ahmadiyeh N, Hu D, Huntsman S, Beckman KB, Caswell JL, et al. Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat Commun. 2014;5:5260. Epub 2014/10/21. ncomms6260 [pii] doi: 10.1038/ncomms6260 25327703; PubMed Central PMCID: PMC4204111.

22. Michailidou K, Lindstrom S, Dennis J, Beesley J, Hui S, Kar S, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551(7678):92–4. doi: 10.1038/nature24284 29059683; PubMed Central PMCID: PMC5798588.

23. Anderson L. Identification of mitochondrial proteins and some of their precursors in two-dimensional electrophoretic maps of human cells. Proc Natl Acad Sci U S A. 1981;78(4):2407–11. Epub 1981/04/01. doi: 10.1073/pnas.78.4.2407 6941300; PubMed Central PMCID: PMC319355.

24. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005;6(5):389–402. doi: 10.1038/nrg1606 15861210.

25. Hervouet E, Simonnet H, Godinot C. Mitochondria and reactive oxygen species in renal cancer. Biochimie. 2007;89(9):1080–8. doi: 10.1016/j.biochi.2007.03.010 17466430.

26. Kujoth GC, Prolla TA. Evolving insight into the role of mitochondrial DNA mutations in aging. Exp Gerontol. 2008;43(1):20–3. doi: 10.1016/j.exger.2007.09.010 18054193.

27. Jackson AL, Loeb LA. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res. 2001;477(1–2):7–21. doi: 10.1016/s0027-5107(01)00091-4 11376682.

28. Lee HC, Yin PH, Lin JC, Wu CC, Chen CY, Wu CW, et al. Mitochondrial genome instability and mtDNA depletion in human cancers. Ann N Y Acad Sci. 2005;1042:109–22. doi: 10.1196/annals.1338.011 15965052.

29. Marcelino LA, Thilly WG. Mitochondrial mutagenesis in human cells and tissues. Mutat Res. 1999;434(3):177–203. doi: 10.1016/s0921-8777(99)00028-2 10486591.

30. Beal MF. Mitochondria, free radicals, and neurodegeneration. Curr Opin Neurobiol. 1996;6(5):661–6. doi: 10.1016/s0959-4388(96)80100-0 8937831.

31. Croteau DL, Bohr VA. Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J Biol Chem. 1997;272(41):25409–12. doi: 10.1074/jbc.272.41.25409 9325246.

32. Lightowlers RN, Chinnery PF, Turnbull DM, Howell N. Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet. 1997;13(11):450–5. doi: 10.1016/s0168-9525(97)01266-3 9385842.

33. Canter JA, Kallianpur AR, Parl FF, Millikan RC. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res. 2005;65(17):8028–33. Epub 2005/09/06. 65/17/8028 [pii] doi: 10.1158/0008-5472.CAN-05-1428 16140977.

34. Mosquera-Miguel A, Alvarez-Iglesias V, Carracedo A, Salas A, Vega A, Milne R, et al. Is mitochondrial DNA variation associated with sporadic breast cancer risk? Cancer Res. 2008;68(2):623–5; author reply 4. Epub 2008/01/18. 68/2/623 [pii] doi: 10.1158/0008-5472.CAN-07-2385 18199560.

35. Francis A, Pooja S, Rajender S, Govindaraj P, Tipirisetti NR, Surekha D, et al. A mitochondrial DNA variant 10398G>A in breast cancer among South Indians: an original study with meta-analysis. Mitochondrion. 2013;13(6):559–65. Epub 2013/09/03. S1567-7249(13)00237-7 [pii] doi: 10.1016/j.mito.2013.08.004 23993954.

36. Bonilla C, Bertoni B, Hidalgo PC, Artagaveytia N, Ackermann E, Barreto I, et al. Breast cancer risk and genetic ancestry: a case-control study in Uruguay. BMC Womens Health. 2015;15:11. Epub 2015/03/19. doi: 10.1186/s12905-015-0171-8 25783644; PubMed Central PMCID: PMC4341228.

37. Blein S, Bardel C, Danjean V, McGuffog L, Healey S, Barrowdale D, et al. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res. 2015;17:61. Epub 2015/05/01. doi: 10.1186/s13058-015-0567-2 [pii]. 25925750; PubMed Central PMCID: PMC4478717.

38. Covarrubias D, Bai RK, Wong LJ, Leal SM. Mitochondrial DNA variant interactions modify breast cancer risk. J Hum Genet. 2008;53(10):924–8. Epub 2008/08/19. doi: 10.1007/s10038-008-0331-x 18709563; PubMed Central PMCID: PMC2767522.

39. Pezzotti A, Kraft P, Hankinson SE, Hunter DJ, Buring J, Cox DG. The mitochondrial A10398G polymorphism, interaction with alcohol consumption, and breast cancer risk. PLoS One. 2009;4(4):e5356. Epub 2009/04/25. doi: 10.1371/journal.pone.0005356 19390621; PubMed Central PMCID: PMC2668794.

40. Setiawan VW, Chu LH, John EM, Ding YC, Ingles SA, Bernstein L, et al. Mitochondrial DNA G10398A variant is not associated with breast cancer in African-American women. Cancer Genet Cytogenet. 2008;181(1):16–9. Epub 2008/02/12. S0165-4608(07)00709-1 [pii] doi: 10.1016/j.cancergencyto.2007.10.019 18262047; PubMed Central PMCID: PMC3225405.

41. Bai RK, Leal SM, Covarrubias D, Liu A, Wong LJ. Mitochondrial genetic background modifies breast cancer risk. Cancer Res. 2007;67(10):4687–94. Epub 2007/05/19. 67/10/4687 [pii] doi: 10.1158/0008-5472.CAN-06-3554 17510395.

42. Gallardo ME, Moreno-Loshuertos R, Lopez C, Casqueiro M, Silva J, Bonilla F, et al. m.6267G>A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors. Hum Mutat. 2006;27(6):575–82. doi: 10.1002/humu.20338 16671096.

43. Kolonel LN, Henderson BE, Hankin JH, Nomura AM, Wilkens LR, Pike MC, et al. A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics. Am J Epidemiol. 2000;151(4):346–57. doi: 10.1093/oxfordjournals.aje.a010213 10695593.

44. Li Y, Beckman KB, Caberto C, Kazma R, Lum-Jones A, Haiman CA, et al. Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort. PLoS One. 2015;10(9):e0136796. Epub 2015/09/05. doi: 10.1371/journal.pone.0136796 PONE-D-15-26620 [pii]. 26340450; PubMed Central PMCID: PMC4560485.

45. Cheng I, Chen GK, Nakagawa H, He J, Wan P, Laurie CC, et al. Evaluating genetic risk for prostate cancer among Japanese and Latinos. Cancer Epidemiol Biomarkers Prev. 2012;21(11):2048–58. doi: 10.1158/1055-9965.EPI-12-0598 22923026; PubMed Central PMCID: PMC3494732.

46. Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X. Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet. 2011;89(1):82–93. Epub 2011/07/09. S0002-9297(11)00222-9 [pii] doi: 10.1016/j.ajhg.2011.05.029 21737059; PubMed Central PMCID: PMC3135811.

47. Ionita-Laza I, Lee S, Makarov V, Buxbaum JD, Lin X. Sequence kernel association tests for the combined effect of rare and common variants. Am J Hum Genet. 2013;92(6):841–53. Epub 2013/05/21. S0002-9297(13)00176-6 [pii] doi: 10.1016/j.ajhg.2013.04.015 23684009; PubMed Central PMCID: PMC3675243.

48. Kosoy R, Nassir R, Tian C, White PA, Butler LM, Silva G, et al. Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. Human Mutation. 2009;30(1):69–78. doi: 10.1002/humu.20822 18683858

49. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38(8):904–9. Epub 2006/07/25. ng1847 [pii] doi: 10.1038/ng1847 16862161.

50. van Oven M, Kayser M. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat. 2009;30(2):E386–94. Epub 2008/10/15. doi: 10.1002/humu.20921 18853457.

51. Kloss-Brandstatter A, Pacher D, Schonherr S, Weissensteiner H, Binna R, Specht G, et al. HaploGrep: a fast and reliable algorithm for automatic classification of mitochondrial DNA haplogroups. Hum Mutat. 2011;32(1):25–32. Epub 2010/10/21. doi: 10.1002/humu.21382 20960467.

52. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A. 2003;100(16):9440–5. Epub 2003/07/29. doi: 10.1073/pnas.1530509100 1530509100 [pii]. 12883005; PubMed Central PMCID: PMC170937.

53. Singh R, Parveen M, Basgen JM, Fazel S, Meshesha MF, Thames EC, et al. Increased Expression of Beige/Brown Adipose Markers from Host and Breast Cancer Cells Influence Xenograft Formation in Mice. Mol Cancer Res. 2016;14(1):78–92. doi: 10.1158/1541-7786.MCR-15-0151 26464213; PubMed Central PMCID: PMC4749269.

54. Lamb R, Ozsvari B, Bonuccelli G, Smith DL, Pestell RG, Martinez-Outschoorn UE, et al. Dissecting tumor metabolic heterogeneity: Telomerase and large cell size metabolically define a sub-population of stem-like, mitochondrial-rich, cancer cells. Oncotarget. 2015;6(26):21892–905. doi: 10.18632/oncotarget.5260 26323205; PubMed Central PMCID: PMC4673134.

55. Cohen T, Levin L, Mishmar D. Ancient Out-of-Africa Mitochondrial DNA Variants Associate with Distinct Mitochondrial Gene Expression Patterns. PLoS Genet. 2016;12(11):e1006407. doi: 10.1371/journal.pgen.1006407 27812116; PubMed Central PMCID: PMC5094714.

56. Leigh-Brown S, Enriquez JA, Odom DT. Nuclear transcription factors in mammalian mitochondria. Genome Biol. 2010;11(7):215. doi: 10.1186/gb-2010-11-7-215 20670382; PubMed Central PMCID: PMC2926779.

57. She H, Yang Q, Shepherd K, Smith Y, Miller G, Testa C, et al. Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients. J Clin Invest. 2011;121(3):930–40. doi: 10.1172/JCI43871 21393861; PubMed Central PMCID: PMC3049386.

58. Grober OM, Mutarelli M, Giurato G, Ravo M, Cicatiello L, De Filippo MR, et al. Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation. BMC Genomics. 2011;12:36. doi: 10.1186/1471-2164-12-36 21235772; PubMed Central PMCID: PMC3025958.

59. Wu MC, Kraft P, Epstein MP, Taylor DM, Chanock SJ, Hunter DJ, et al. Powerful SNP-set analysis for case-control genome-wide association studies. Am J Hum Genet. 2010;86(6):929–42. Epub 2010/06/22. S0002-9297(10)00248-X [pii] doi: 10.1016/j.ajhg.2010.05.002 20560208; PubMed Central PMCID: PMC3032061.

60. Saxena R, de Bakker PI, Singer K, Mootha V, Burtt N, Hirschhorn JN, et al. Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. Am J Hum Genet. 2006;79(1):54–61. doi: 10.1086/504926 16773565; PubMed Central PMCID: PMC1474138.

61. Ali AT, Boehme L, Carbajosa G, Seitan VC, Small KS, Hodgkinson A. Nuclear genetic regulation of the human mitochondrial transcriptome. Elife. 2019;8. doi: 10.7554/eLife.41927 30775970; PubMed Central PMCID: PMC6420317.