Tumor Biology

, Volume 36, Issue 7, pp 5369–5376 | Cite as

Association of microRNA 17–92 cluster host gene (MIR17HG) polymorphisms with breast cancer

  • Diego Chacon-Cortes
  • Robert A. Smith
  • Rodney A. Lea
  • Philippa H. Youl
  • Lyn R. GriffithsEmail author
Research Article


Breast cancer incidence and mortality rates are increasing despite our current knowledge on the disease. Ninety-five percent of breast cancer cases correspond to sporadic forms of the disease and are believed to involve an interaction between environmental and genetic determinants. The microRNA 17–92 cluster host gene (MIR17HG) has been shown to regulate expression of genes involved in breast cancer development and progression. Study of single-nucleotide polymorphisms (SNPs) located in this cluster gene could help provide a further understanding of its role in breast cancer. Therefore, this study investigated six SNPs in the MIR17HG using two independent Australian Caucasian case–control populations (GRC-BC and GU-CCQ BB populations) to determine association to breast cancer susceptibility. Genotyping was undertaken using chip-based matrix assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry (MS). We found significant association between rs4824505 and breast cancer at the allelic level in both study cohorts (GRC-BC p = 0.01 and GU-CCQ BB p = 0.03). Furthermore, haplotypic analysis of results from our combined population determined a significant association between rs4824505/rs7336610 and breast cancer susceptibility (p = 5 × 10−4). Our study is the first to show that the A allele of rs4824505 and the AC haplotype of rs4824505/rs7336610 are associated with risk of breast cancer development. However, definitive validation of this finding requires larger cohorts or populations in different ethnical backgrounds. Finally, functional studies of these SNPs could provide a deeper understanding of the role that MIR17HG plays in the pathophysiology of breast cancer.


Association analysis Breast cancer Haplotype MicroRNA Single nucleotide polymorphisms (SNP) 



This research was funded by research grants from the Griffith Health Institute, the Cancer Council Queensland and funding from the national Health and Medical Research Council. Blood samples from the Griffith University-Cancer Council Queensland Biobank were collected from patients enrolled in Cancer Council Queensland’s Breast Cancer Outcomes Study funded by a Cancer Australia grant (no. 1006339). Dr Youl is supported by an NHMRC Early Career Research Fellowship (no. 1054038). We thank Professor Suzanne K. Chambers for her assistance in the development of this project. In addition, this study used infrastructure provided by the Australian government EIF Super Science Funds as part of the Therapeutic Innovation Australia—Queensland node project.


  1. 1.
    Ferlay J SI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer. 2013. Accessed 22/08/2012.
  2. 2.
    Stewart BW, Wild C. International Agency for Research on C, World Health O. World cancer report 2014. vol book, whole. Lyon, France: International Agency for Research on Cancer; 2014.Google Scholar
  3. 3.
    Robbins SL, Kumar V, Cotran RS. Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Saunders/Elsevier; 2010.Google Scholar
  4. 4.
    Anderson DE. Familial versus sporadic breast cancer. Cancer. 1992;70(6 Suppl):1740–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996;77(11):2318–24. doi: 10.1002/(sici)1097-0142(19960601)77:11<2318::aid-cncr21>;2-z.CrossRefPubMedGoogle Scholar
  6. 6.
    Martin A-M, Weber BL. Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst. 2000;92(14):1126–35. doi: 10.1093/jnci/92.14.1126.CrossRefPubMedGoogle Scholar
  7. 7.
    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66. doi: 10.1038/nrc1997.CrossRefPubMedGoogle Scholar
  8. 8.
    Lynam-Lennon N, Maher SG, Reynolds JV. The roles of microRNA in cancer and apoptosis. Biol Rev. 2009;84(1):55–71. doi: 10.1111/j.1469-185X.2008.00061.x.CrossRefPubMedGoogle Scholar
  9. 9.
    Yu Z, Baserga R, Chen L, Wang C, Lisanti MP, Pestell RG. MicroRNA, cell cycle, and human breast cancer. Am J Pathol. 2010;176(3):1058–64. doi: 10.2353/ajpath.2010.090664.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Farazi TA, Spitzer JI, Morozov P, Tuschl T. miRNAs in human cancer. J Pathol. 2011;223(2):102–15.CrossRefPubMedGoogle Scholar
  11. 11.
    Lee Y, Jeon K, Lee JT, Kim S, Kim VN. MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 2002;21(17):4663–70.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J et al. The nuclear RNase III Drosha initiates microRNA processing. Nature Publishing Group; 2003. p. 415.Google Scholar
  13. 13.
    Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003;17(24):3011–6. doi: 10.1101/gad.1158803.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005;436(7051):740–4. doi: 10.1038/nature03868.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rajewsky N. microRNA target predictions in animals. Nat Genet. 2006.Google Scholar
  17. 17.
    Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15(8):509–24. doi: 10.1038/nrm3838.CrossRefPubMedGoogle Scholar
  18. 18.
    Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005;6(5):376–85. doi: 10.1038/nrm1644.CrossRefPubMedGoogle Scholar
  19. 19.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101(9):2999–3004. doi: 10.1073/pnas.0307323101.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ota A, Tagawa H, Karnan S, Tsuzuki S, Karpas A, Kira S, et al. Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res. 2004;64(9):3087–95.CrossRefPubMedGoogle Scholar
  21. 21.
    Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132(5):875–86. doi: 10.1016/j.cell.2008.02.019.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435(7043):828–33. doi: 10.1038/nature03552.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435(7043):839–43. doi: 10.1038/nature03677.CrossRefPubMedGoogle Scholar
  24. 24.
    Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17–92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65(21):9628–32. doi: 10.1158/0008-5472.CAN-05-2352.CrossRefPubMedGoogle Scholar
  25. 25.
    Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 2013;20(12):1603–14. doi: 10.1038/cdd.2013.125.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Olive V, Jiang I, He L. mir-17–92, a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol. 2010;42(8):1348–54. doi: 10.1016/j.biocel.2010.03.004.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hossain A, Kuo MT, Saunders GF. Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol Cell Biol. 2006;26(21):8191–201. doi: 10.1128/MCB. 00242-06.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yu Z, Wang C, Wang M, Li Z, Casimiro MC, Liu M, et al. A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J Cell Biol. 2008;182(3):509–17. doi: 10.1083/jcb.200801079.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Leivonen SK, Makela R, Ostling P, Kohonen P, Haapa-Paananen S, Kleivi K, et al. Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines. Oncogene. 2009;28(44):3926–36. doi: 10.1038/onc.2009.241.CrossRefPubMedGoogle Scholar
  30. 30.
    Youl PH, Baade PD, Aitken JF, Chambers SK, Turrell G, Pyke C, et al. A multilevel investigation of inequalities in clinical and psychosocial outcomes for women after breast cancer. BMC Cancer. 2011;11:415. doi: 10.1186/1471-2407-11-415.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65. doi: 10.1038/nature11632.CrossRefPubMedGoogle Scholar
  32. 32.
    Chacon-Cortes D, Haupt L, Lea R, Griffiths L. Comparison of genomic DNA extraction techniques from whole blood samples: a time, cost and quality evaluation study. Mol Biol Rep. 2012;39(5):5961–6. doi: 10.1007/s11033-011-1408-8.CrossRefPubMedGoogle Scholar
  33. 33.
    Nasiri H, Forouzandeh M, Rasaee MJ, Rahbarizadeh F. Modified salting-out method: high-yield, high-quality genomic DNA extraction from whole blood using laundry detergent. J Clin Lab Anal. 2005;19(6):229–32.CrossRefPubMedGoogle Scholar
  34. 34.
    Chacon-Cortes D, Griffiths L. Methods for extracting genomic DNA from whole blood samples: current perspectives. J Biorepository Sci Appl Med. 2014;2:1–9.Google Scholar
  35. 35.
    Huberman JA. Importance of measuring nucleic acid absorbance at 240 nm as well as at 260 and 280 nm. Biotechniques. 1995;18(4):636.PubMedGoogle Scholar
  36. 36.
    Sahota A, Brooks AI, Tischfield JA, King IB. Preparing DNA from blood for genotyping. CSH Protocol. 2007. doi: 10.1101/pdb.prot4830.Google Scholar
  37. 37.
    Sambrook J, Russell DW. Molecular cloning: a laboratory manual. 1st ed. New York: Cold Spring Harbor Laboratory Press; 2001.Google Scholar
  38. 38.
    Lu M, Zhang Q, Deng M, Miao J, Guo Y, Gao W, et al. An analysis of human microRNA and disease associations. PLoS One. 2008;3(10):e3420. doi: 10.1371/journal.pone.0003420.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Guo SW, Thompson EA. Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics. 1992;48(2):361–72.CrossRefPubMedGoogle Scholar
  41. 41.
    Hardy GH. Mendelian proportions in a mixed population. Science. 1908;28(706):49–50.CrossRefPubMedGoogle Scholar
  42. 42.
    Fisher SRA, Yates F. Statistical tables for biological, agricultural and medical research. London: Oliver & Boyd; 1963. revised and enlarged.Google Scholar
  43. 43.
    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75. doi: 10.1086/519795.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5. doi: 10.1093/bioinformatics/bth457.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Diego Chacon-Cortes
    • 1
    • 2
  • Robert A. Smith
    • 1
    • 2
  • Rodney A. Lea
    • 1
    • 2
  • Philippa H. Youl
    • 2
    • 3
    • 4
  • Lyn R. Griffiths
    • 1
    • 2
    Email author
  1. 1.Genomics Research Centre, Institute of Health and Biomedical InnovationQueensland University of TechnologyBrisbaneAustralia
  2. 2.Griffith Health InstituteGriffith UniversityBrisbaneAustralia
  3. 3.Cancer Council QueenslandBrisbaneAustralia
  4. 4.School of Public HealthQueensland University of TechnologyBrisbaneAustralia

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