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A genetic variant at 12p11 significantly modifies breast cancer risk in a genetically homogenous island population

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Abstract

Genome-wide association studies have identified novel breast cancer susceptibility loci at 12q24 (rs1292011), 12p11 (rs10771399) and 21q21 (rs2823093). The aim of our study was to investigate the prevalence of variants at these three loci in an Irish sample, and to examine the association between these variants and breast cancer in this cohort. DNA was extracted from the blood or buccal swabs of Irish patients with breast cancer (cases), as well as from healthy Irish female controls. Genotyping was performed for each target using a Taqman-based platform. Data were analysed using IBM Statistical Package for the Social Sciences version 22. Genotyping was performed on samples from 1,267 patients with breast cancer and 841 cancer-free controls. The per-allele odds ratio associated with the minor allele at 12p11 was found to be 0.67 (0.54–0.81, p < 0.001). Genotype-specific odds ratios showed an allele dosage effect with odds ratio of 0.76 (0.6–0.95) for heterozygotes, and 0.23 (0.1–0.51) for rare homozygotes. Minor allele frequencies of the variants at 12q24 and 21q21 did not differ significantly between cases or controls. All three investigated variants were identified in the Irish population. The polymorphism rs10771399 was strongly associated with breast cancer risk in this cohort, and was shown to be associated with reduced odds ratio for all molecular subtypes.

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References

  1. Ponder BAJ, Day NE, Easton DF, Pharoah PDP, Lipscombe JM, Redman K, Antoniou A, Basham V, Gregory J, Gayther S, Dunning A (2000) Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 83(10):1301–1308

    Article  Google Scholar 

  2. Smith P, McGuffog L, Easton DF et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45(7):646–655

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Pharoah PDP, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BAJ (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31(1):33–36

    Article  CAS  PubMed  Google Scholar 

  4. Ghoussaini M, Pharoah PDP, Easton DF (2013) Inherited genetic susceptibility to breast cancer: the beginning of the end or the end of the beginning? Am J Pathol 183(4):1038–1051

    Article  CAS  PubMed  Google Scholar 

  5. Ghoussaini M, Fletcher O, Michailidou K et al (2012) Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 44(3):312–318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. http://apps.ccge.medschl.cam.ac.uk/consortia/bcac//groups/groups.html

  7. Horwitz MJ, Stewart AF (2006) Hypercalcemia associated with malignancy. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th edn. American Society of Bone and Mineral Research, Washington DC

    Google Scholar 

  8. Sloan EK, Anderson RL (2002) Genes involved in breast cancer metastasis to bone. Cell Mol Life Sci 59(9):1491–1502

    Article  CAS  PubMed  Google Scholar 

  9. Mula RV, Bhatia V, Falzon M (2010) PTHrP promotes colon cancer cell migration and invasion in an integrin alpha6beta4-dependent manner through activation of Rac1. Cancer Lett 298(1):119–127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Qin Z, Wang Y, Cao S, He Y, Ma H, Jin G, Hu Z, Guan X, Shen H (2013) Genetic variants at 12p11 and 12q24 are associated with breast cancer risk in a Chinese population. PLoS ONE 8(6):e66519

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Antoniou AC, Kuchenbaecker KB, Soucy P et al (2012) Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast Cancer Res 14(1):R33

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Lin J, Ding L, Jin R, Zhang H, Cheng L, Qin X, Chai J, Ye Q (2009) Four and a half LIM domains 1 (FHL1) and receptor interacting protein of 140 kDa (RIP140) interact and cooperate in estrogen signaling. Int J Biochem Cell Biol 41(7):1613–1618

    Article  CAS  PubMed  Google Scholar 

  13. McVeigh TP, Irwin R, Cody N, Miller N, McDevitt T, Sweeney KJ, Green AJ, Kerin MJ (2014) Familial breast cancer genetic testing in the West of Ireland. Ir J Med Sci 183(2):199–206

    Article  CAS  PubMed  Google Scholar 

  14. Beral V, Bull D, Doll R, Peto R, Reeves G (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389–1399

    Article  Google Scholar 

  15. Shapiro SS (1964) An analysis of variance test for normality (complete samples)

  16. Rodriguez S, Gaunt TR, Day INM (2009) Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 169(4):505–514

    Article  PubMed Central  PubMed  Google Scholar 

  17. Evans DG, Lalloo F, Wallace A, Rahman N (2005) Update on the Manchester scoring system for BRCA1 and BRCA2 testing. J Med Genet 42(7):e39

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Bland JM, Altman DG (2000) Statistics notes. The odds ratio. BMJ 320(7247):1468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Online Sample Size Estimator, Bioinformatics institute http://osse.bii.a-star.edu.sg/index.php

  20. Chen YC, Hunter DJ (2005) Molecular epidemiology of cancer. CA Cancer J Clin 55(1):45–54

    Article  PubMed  Google Scholar 

  21. Narod SA (2006) Modifiers of risk of hereditary breast cancer. Oncogene 25(43):5832–5836

    Article  CAS  PubMed  Google Scholar 

  22. O’Dushlaine CT, Morris D, Moskvina V, Kirov G, Gill M, Corvin A, Wilson JF, Cavalleri GL (2010) Population structure and genome-wide patterns of variation in Ireland and Britain. Eur J Hum Genet 18(11):1248–1254

    Article  PubMed Central  PubMed  Google Scholar 

  23. Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, Nelson MR, Stephens M, Bustamante CD (2008) Genes mirror geography within Europe. Nature 456(7218):98–101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Moore LT, McEvoy B, Cape E, Simms K, Bradley DG (2006) A Y-chromosome signature of hegemony in Gaelic Ireland. Am J Hum Genet 78(2):334–338

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Hill EW, Jobling MA, Bradley DG (2000) Y-chromosome variation and Irish origins. Nature 404(6776):351–352

    Article  CAS  PubMed  Google Scholar 

  26. Saugstad LF (1975) Anthropological significance of phenylketonuria. Clin Genet 7(1):52–61

    Article  CAS  PubMed  Google Scholar 

  27. Coss KP, Doran PP, Owoeye C, Codd MB, Hamid N, Mayne PD, Crushell E, Knerr I, Monavari AA, Treacy EP (2013) Classical galactosaemia in Ireland: incidence, complications and outcomes of treatment. J Inherit Metab Dis 36(1):21–27

    Article  CAS  PubMed  Google Scholar 

  28. Farrell PM, Joffe S, Foley L, Canny GJ, Mayne P, Rosenberg M (2007) Diagnosis of cystic fibrosis in the Republic of Ireland: epidemiology and costs. Ir Med J 100(8):557

    CAS  PubMed  Google Scholar 

  29. Ryan E, O’Keane C, Crowe J (1998) Hemochromatosis in Ireland and HFE. Blood Cells Mol Dis 24(4):428–432

    Article  CAS  PubMed  Google Scholar 

  30. Eisensmith RC, Goltsov AA, O’Neill C et al (1995) Recurrence of the R408 W mutation in the phenylalanine hydroxylase locus in Europeans. Am J Hum Genet 56(1):278–286

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Ramus SJ, Treacy EP, Cotton RGH (1995) Characterization of phenylalanine hydroxylase alleles in untreated phenylketonuria patients from Victoria, Australia: origin of alleles and haplotypes. Am J Hum Genet 56(5):1034–1041

    CAS  PubMed Central  PubMed  Google Scholar 

  32. American Community Survey, 2012, 1-year estimates. http://www.census.gov/

  33. Australian Bureau of Statistics, The average Australian. http://www.abs.gov.au/AUSSTATS/abs@.nsf/Lookup/4102.0Main+Features30April+2013

  34. Vallone PM, Butler JM (2004) Y-SNP typing of U.S. African American and Caucasian samples using allele-specific hybridization and primer extension. J Forensic Sci 49(4):723–732

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded with thanks by the National Breast Cancer Research Institute (NBCRI) and supplemented by a summer student scholarship from the Health Research Board (HRB, granted to Una McVeigh).

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The authors declare that they have no conflict of interest.

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Correspondence to Terri Patricia McVeigh.

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McVeigh, T.P., McVeigh, U.M., Sweeney, K.J. et al. A genetic variant at 12p11 significantly modifies breast cancer risk in a genetically homogenous island population. Breast Cancer Res Treat 149, 41–47 (2015). https://doi.org/10.1007/s10549-014-3222-1

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  • DOI: https://doi.org/10.1007/s10549-014-3222-1

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