Breast Cancer Research and Treatment

, Volume 128, Issue 1, pp 267–272 | Cite as

Replication of genome-wide discovered breast cancer risk loci in the Cypriot population

  • Maria A. Loizidou
  • Andreas Hadjisavvas
  • John P. A. Ioannidis
  • Kyriacos Kyriacou
Epidemiology

Abstract

Genome-wide association studies (GWAS) have identified associations with robust statistical support for influencing breast cancer susceptibility. Most GWAS and replications have been conducted in Northern European populations and to a lesser extent in Asians, and Ashkenazi Jews. It is important to evaluate whether these variants confer risk across different populations and also to assess the magnitude of risk conferred. The aim of this study was to evaluate previously GWAS-identified breast cancer risk variants in the Cypriot population. Eleven GWAS-discovered single nucleotide polymorphisms (SNPs) were analyzed for association with breast cancer in 1,109 Cypriot female breast cancer patients and 1,177 healthy female controls. Four of the 11 SNPs evaluated were found to be nominally significantly associated (P < 0.05) with breast cancer risk in the Cypriot population. Based on estimated power, five associations would be expected to be nominally significant. The correlation coefficient of effect sizes (per-allele odds ratio) between the Cypriot population and the original GWAS populations where these SNPs had been discovered was 0.58 (P = 0.064), while allele frequencies were very similar (r = 0.88, P < 0.001). Overall, we show modest concordance for breast cancer GWAS-discovered alleles and their effect sizes in the Cypriot population. The effects sizes of GWAS-discovered SNPs need to be verified separately in different populations.

Keywords

Breast cancer Cyprus GWAS replication SNP 

Notes

Acknowledgments

The authors thank Drs Yiola Marcou, Eleni Kakouri, Maria Daniel, Panayiotis Papadopoulos, and Simon Malas for their assistance in recruiting breast cancer patients. The authors also thank Rena Papachristoforou and Thalia Michael for their assistance in data collection, and Christina Flouri and Ioanna Neophytou for help with genotyping. The authors are indebted to all study participants. This study is co-funded by the Republic of Cyprus through Cyprus Research Promotion Foundation, the European Union Regional Development Structural Funds (Grant:ΥΓΕΙΑ/ΒΙΟΣ/0308 (ΒΙΕ)/08) and the Cyprus Institute of Neurology and Genetics.

Conflict of interest

None

Supplementary material

10549_2010_1319_MOESM1_ESM.doc (102 kb)
Supplementary material 1 (DOC 101 kb)

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33(Suppl):238–244PubMedCrossRefGoogle Scholar
  3. 3.
    Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40:17–22PubMedCrossRefGoogle Scholar
  4. 4.
    Houlston RS, Peto J (2004) The search for low-penetrance cancer susceptibility alleles. Oncogene 23:6471–6476PubMedCrossRefGoogle Scholar
  5. 5.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71PubMedCrossRefGoogle Scholar
  6. 6.
    Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792PubMedCrossRefGoogle Scholar
  7. 7.
    Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130PubMedCrossRefGoogle Scholar
  8. 8.
    Smith P, McGuffog L, Easton DF, Mann GJ, Pupo GM, Newman B, Chenevix-Trench G, Szabo C, Southey M, Renard H et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45:646–655PubMedCrossRefGoogle Scholar
  9. 9.
    Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36PubMedCrossRefGoogle Scholar
  10. 10.
    Galvan A, Ioannidis JP, Dragani TA (2010) Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer. Trends Genet 26:132–141PubMedCrossRefGoogle Scholar
  11. 11.
    Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870–874PubMedCrossRefGoogle Scholar
  12. 12.
    Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093PubMedCrossRefGoogle Scholar
  13. 13.
    Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, Masson G, Jakobsdottir M, Thorlacius S, Helgason A et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869PubMedCrossRefGoogle Scholar
  14. 14.
    Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber J, Friedman E, Narod S, Olshen AB, Gregersen P et al (2008) Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci USA 105:4340–4345PubMedCrossRefGoogle Scholar
  15. 15.
    Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, Jonsson GF, Jakobsdottir M, Bergthorsson JT, Gudmundsson J, Aben KK et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40:703–706PubMedCrossRefGoogle Scholar
  16. 16.
    Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, Wen W, Levy S, Deming SL, Haines JL et al (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41:324–328PubMedCrossRefGoogle Scholar
  17. 17.
    Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K et al (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (rad51l1). Nat Genet 41:579–584PubMedCrossRefGoogle Scholar
  18. 18.
    Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41:585–590PubMedCrossRefGoogle Scholar
  19. 19.
    Ioannidis JP, Castaldi P, Evangelou E (2010) A compendium of genome-wide associations for cancer: critical synopsis and reappraisal. J Natl Cancer Inst 102:846–858PubMedCrossRefGoogle Scholar
  20. 20.
    Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42:504–507PubMedCrossRefGoogle Scholar
  21. 21.
    Ioannidis JP (2009) Population-wide generalizability of genome-wide discovered associations. J Natl Cancer Inst 101:1297–1299PubMedCrossRefGoogle Scholar
  22. 22.
    Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, Nelson MR et al (2008) Genes mirror geography within Europe. Nature 456:98–101PubMedCrossRefGoogle Scholar
  23. 23.
    Hoggart CJ, Clark TG, De Iorio M, Whittaker JC, Balding DJ (2008) Genome-wide significance for dense snp and resequencing data. Genet Epidemiol 32(2):179–185PubMedCrossRefGoogle Scholar
  24. 24.
    The International Hapmap Consortium (2003) The international hapmap project. Nature 426:789–796Google Scholar
  25. 25.
    Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) Snpstats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929PubMedCrossRefGoogle Scholar
  26. 26.
    Dupont WD, Plummer WD Jr (1990) Power and sample size calculations. A review and computer program. Control Clin Trials 11:116–128PubMedCrossRefGoogle Scholar
  27. 27.
    Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J et al (2009) Strengthening the reporting of genetic association studies (strega): an extension of the strobe statement. PLoS Med 6(2):e22PubMedCrossRefGoogle Scholar
  28. 28.
    Kirchhoff T, Chen ZQ, Gold B, Pal P, Gaudet MM, Kosarin K, Levine DA, Gregersen P, Spencer S, Harlan M et al (2009) The 6q22.33 locus and breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 18:2468–2475PubMedCrossRefGoogle Scholar
  29. 29.
    Salanti G, Southam L, Altshuler D, Ardlie K, Barroso I, Boehnke M, Cornelis MC, Frayling TM, Grallert H, Grarup N et al (2009) Underlying genetic models of inheritance in established type 2 diabetes associations. Am J Epidemiol 170:537–545PubMedCrossRefGoogle Scholar
  30. 30.
    Pereira TV, Patsopoulos NA, Salanti G, Ioannidis JP (2009) Discovery properties of genome-wide association signals from cumulatively combined data sets. Am J Epidemiol 170:1197–1206PubMedCrossRefGoogle Scholar
  31. 31.
    Gail MH (2009) Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model. J Natl Cancer Inst 101:959–963PubMedCrossRefGoogle Scholar
  32. 32.
    Thomas DC, Witte JS (2002) Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev 11:505–512PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Maria A. Loizidou
    • 1
  • Andreas Hadjisavvas
    • 1
    • 2
  • John P. A. Ioannidis
    • 3
    • 4
    • 5
  • Kyriacos Kyriacou
    • 1
  1. 1.Department of Electron Microscope / Molecular PathologyThe Cyprus Institute of Neurology and GeneticsNicosiaCyprus
  2. 2.Brunel Institute for Cancer Genetics and PharmacogenomicsBrunel UniversityUxbridgeUK
  3. 3.Department of Hygiene and EpidemiologyUniversity of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology-HellasIoanninaGreece
  4. 4.Center for Genetic Epidemiology and ModellingTufts University School of MedicineBostonUSA
  5. 5.Department of EpidemiologyHarvard School of Public HealthBostonUSA

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