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Molecular Biology Reports

, Volume 41, Issue 6, pp 3715–3722 | Cite as

Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population

  • Isabel Elematore
  • Patricio Gonzalez-Hormazabal
  • Jose M. Reyes
  • Rafael Blanco
  • Teresa Bravo
  • Octavio Peralta
  • Fernando Gomez
  • Enrique Waugh
  • Sonia Margarit
  • Gladys Ibañez
  • Carmen Romero
  • Janara Pakomio
  • Gigia Roizen
  • Gabriella A. Di Capua
  • Lilian JaraEmail author
Article

Abstract

Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95 %CI 1.02–13.84, P = 0.046) and 8.0 (95 %CI 2.20–29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28–1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.

Keywords

Breast cancer Polymorphisms TOX3 TNRC9 2q35 8q24 

Notes

Acknowledgments

The authors thank the many families who participated in the research studies described in this article. We acknowledge the Breast Cancer Group of CONAC: Maria Teresa Barrios, Angelica Soto, Rossana Recabarren, Leticia Garcia, Karen Olmos and Paola Carrasco; and Lorena Seccia for her technical assistance.

Conflict of interest

Corporación Nacional del Cáncer.

The authors declare that they have no competing interests.

Grant sponsor

Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT). Grant number: 1110081.

References

  1. 1.
    Departamento de Estadísticas e Información en Salud. Defunciones por tumores malignos según sexo, Chile 2000–2010. [http://webdeis.minsal.cl/wp-content/uploads/2012/12/Def_Mort_obs_ajust_tumores_Region_2000-2010.xlsx] Accesed 23 Jan 2013
  2. 2.
    Walsh T, King M (2007) Ten genes for inherited breast cancer. Cancer Cell 11:103–105. doi: 10.1016/j.ccr.2007.01.010 CrossRefPubMedGoogle Scholar
  3. 3.
    Chen M, Wu X, Shen W, Wei M, Li C, Cai B et al (2011) Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects. Breast Cancer Res Treat 126:177–183. doi: 10.1007/s10549-010-1114-6 CrossRefPubMedGoogle Scholar
  4. 4.
    Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40:17–22. doi: 10.1038/ng.2007.53 CrossRefPubMedGoogle Scholar
  5. 5.
    Turnbull C, Rahman N (2008) Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet 9:321–345. doi: 10.1146/annurev.genom.9.081307.164339 CrossRefPubMedGoogle Scholar
  6. 6.
    Pharoah PDP, Antoniou AC, Easton DF, Ponder BAJ (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358:2796–2803. doi: 10.1056/NEJMsa0708739 CrossRefPubMedGoogle Scholar
  7. 7.
    Easton DF, Pooley KA, Dunning AM, Pharoah PDP, Thompson D, Ballinger DG et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093. doi: 10.1038/nature05887 PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Ruiz-Narvaez EA, Rosenberg L, Rotimi CN, Cupples LA, Boggs DA, Adeyemo A et al (2010) Genetic variants on chromosome 5p12 are associated with risk of breast cancer in African American women: the black women’s health study. Breast Cancer Res Treat 123:525–530. doi: 10.1007/s10549-010-0775-5 PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869. doi: 10.1038/ng2064 CrossRefPubMedGoogle Scholar
  10. 10.
    Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870–874. doi: 10.1038/ng2075 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Gorodnova TV, Kuligina ES, Yanus GA, Katanugina AS, Abysheva SN, Togo AV et al (2010) Distribution of FGFR2, TNRC9, MAP3K1, LSP1, and 8q24 alleles in genetically enriched breast cancer patients versus elderly tumor-free women. Cancer Genet Cytogenet 199:69–72. doi: 10.1016/j.cancergencyto.2010.01.020 CrossRefPubMedGoogle Scholar
  12. 12.
    Hemminki K, Müller-Myhsok B, Lichtner P, Engel C, Chen B, Burwinkel B et al (2010) Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients. Int J Cancer 126:2858–2862. doi: 10.1002/ijc.24986 PubMedGoogle Scholar
  13. 13.
    Harlid S, Ivarsson MIL, Butt S, Grzybowska E, Eyfjörd JE, Lenner P et al (2012) Combined effect of low-penetrant SNPs on breast cancer risk. Br J Cancer 106:389–396. doi: 10.1038/bjc.2011.461 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Gonzalez-Hormazabal P, Gutierrez-Enriquez S, Gaete D, Reyes JM, Peralta O, Waugh E et al (2011) Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families. Breast Cancer Res Treat 126:705–716. doi: 10.1007/s10549-010-1170-y CrossRefPubMedGoogle Scholar
  15. 15.
    Gonzalez-Hormazabal P, Reyes JM, Blanco R, Bravo T, Carrera I, Peralta O et al (2012) The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population. Mol Biol Rep 39:8091–8098. doi: 10.1007/s11033-012-1656-2 CrossRefPubMedGoogle Scholar
  16. 16.
    González-Hormazábal P, Bravo T, Blanco R, Valenzuela CY, Gómez F, Waugh E et al (2008) Association of common ATM variants with familial breast cancer in a South American population. BMC Cancer 8:117. doi: 10.1186/1471-2407-8-117 PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    González-Hormazábal P, Castro VG, Blanco R, Gómez F, Peralta O, Waugh E et al (2008) Absence of CHEK2 1100delC mutation in familial breast cancer cases from a South American population. Breast Cancer Res Treat 110:543–545. doi: 10.1007/s10549-007-9743-0 CrossRefPubMedGoogle Scholar
  18. 18.
    Jara L, Acevedo ML, Blanco R, Castro VG, Bravo T, Gómez F et al (2007) RAD51 135G > C polymorphism and risk of familial breast cancer in a South American population. Cancer Genet Cytogenet 178:65–69. doi: 10.1016/j.cancergencyto.2007.05.024 CrossRefPubMedGoogle Scholar
  19. 19.
    Jara L, Dubois K, Gaete D, de Mayo T, Ratkevicius N, Bravo T et al (2010) Variants in dna double-strand break repair genes and risk of familial breast cancer in a South American population. Breast Cancer Res Treat 122:813–822. doi: 10.1007/s10549-009-0709-2 CrossRefPubMedGoogle Scholar
  20. 20.
    Jara L, Gonzalez-Hormazabal P, Cerceño K, Di Capua GA, Reyes JM, Blanco R et al (2013) Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population. Breast Cancer Res Treat 137:559–569. doi: 10.1007/s10549-012-2359-z CrossRefPubMedGoogle Scholar
  21. 21.
    Chomczynski P, Sacchi N (2006) The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat Protoc 1:581–585. doi: 10.1038/nprot.2006.83 CrossRefPubMedGoogle Scholar
  22. 22.
    Greenland S, Lash TL, Rothman KJ (2008) Concepts of Interactions. In: Rothman KJ, Greenland S (eds) Lash TL Modern Epidemiology, 3rd edn. Lippicott Williams & Wilkins, Philadehpia, pp 71–83Google Scholar
  23. 23.
    Hosmer DW, Lemeshow S (1992) Confidence interval estimation of interaction. Epidemiology 3:452–456CrossRefPubMedGoogle Scholar
  24. 24.
    Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL et al (2013) Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 45:353–361. doi: 10.1038/ng.2563 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Zheng W, Cai Q, Signorello LB, Long J, Hargreaves MK, Deming SL et al (2009) Evaluation of 11 breast cancer susceptibility loci in African-American women. Cancer Epidemiol. Biomarkers Prev. 18:2761–2764. doi: 10.1158/1055-9965.EPI-09-0624 PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Smid M, Wang Y, Klijn JGM, Sieuwerts AM, Zhang Y, Atkins D et al (2006) Genes associated with breast cancer metastatic to bone. J Clin Oncol 24:2261–2267. doi: 10.1200/JCO.2005.03.8802 CrossRefPubMedGoogle Scholar
  27. 27.
    Latif A, Hadfield KD, Roberts SA, Shenton A, Lalloo F, Black GCM et al (2010) Breast cancer susceptibility variants alter risks in familial disease. J Med Genet 47:126–131. doi: 10.1136/jmg.2009.067256 CrossRefPubMedGoogle Scholar
  28. 28.
    Udler MS, Ahmed S, Healey CS, Meyer K, Struewing J, Maranian M et al (2010) Fine scale mapping of the breast cancer 16q12 locus. Hum Mol Genet 19:2507–2515. doi: 10.1093/hmg/ddq122 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Riaz M, Berns EMJJ, Sieuwerts AM, Ruigrok-Ritstier K, de Weerd V, Groenewoud A et al (2012) Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes. Breast Cancer Res Treat 133:843–851. doi: 10.1007/s10549-011-1663-3 CrossRefPubMedGoogle Scholar
  30. 30.
    Milne RL, Benítez J, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C et al (2009) Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042. J Natl Cancer Inst 101:1012–1018. doi: 10.1093/jnci/djp167 PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Dai J, Hu Z, Jiang Y, Shen H, Dong J, Ma H et al (2012) Breast cancer risk assessment with five independent genetic variants and two risk factors in chinese women. Breast Cancer Res 14:R17. doi: 10.1186/bcr3101 PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Lin C, Ho C, Bau D, Yang S, Liu S, Lin P et al (2012) Evaluation of breast cancer susceptibility loci on 2q35, 3p24, 17q23 and F2 genes in taiwanese women with breast cancer. Anticancer Res 32:475–482PubMedGoogle Scholar
  33. 33.
    Huo D, Zheng Y, Ogundiran TO, Adebamowo C, Nathanson KL, Domchek SM et al (2012) Evaluation of 19 susceptibility loci of breast cancer in women of african ancestry. Carcinogenesis 33:835–840. doi: 10.1093/carcin/bgs093 PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Long J, Shu X, Cai Q, Gao Y, Zheng Y, Li G et al (2010) Evaluation of breast cancer susceptibility loci in chinese women. Cancer Epidemiol. Biomarkers Prev. 19:2357–2365. doi: 10.1158/1055-9965.EPI-10-0054 PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Cruz-Coke R (1976) Origen y evolución étnica de la población chilena. Rev Med Chil 104:365–368PubMedGoogle Scholar
  36. 36.
    Valenzuela C (1988) On sociogenetic clines. Ethol Sociobiol 9:259–268CrossRefGoogle Scholar
  37. 37.
    Valenzuela C, Harb Z (1977) Socioeconomic assortative mating in santiago, chile: as demonstrated using stochastic matrices of mother-child relationships applied to abo blood groups. Soc Biol 24:225–233CrossRefPubMedGoogle Scholar
  38. 38.
    Valenzuela CY, Acuña MP, Harb Z (1987) sociogenetic gradient in the chilean population. Rev Med Chil 115:295–299PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Isabel Elematore
    • 1
  • Patricio Gonzalez-Hormazabal
    • 1
  • Jose M. Reyes
    • 2
  • Rafael Blanco
    • 1
  • Teresa Bravo
    • 3
  • Octavio Peralta
    • 2
    • 4
  • Fernando Gomez
    • 5
  • Enrique Waugh
    • 5
  • Sonia Margarit
    • 6
  • Gladys Ibañez
    • 7
    • 8
  • Carmen Romero
    • 9
  • Janara Pakomio
    • 1
  • Gigia Roizen
    • 1
  • Gabriella A. Di Capua
    • 1
  • Lilian Jara
    • 1
    Email author
  1. 1.Human Genetics Program, Institute of Biomedical Sciences (ICBM)School of Medicine, University of ChileSantiagoChile
  2. 2.Clínica Las CondesSantiagoChile
  3. 3.National Cancer Society (Corporación Nacional del Cáncer –CONAC-)SantiagoChile
  4. 4.Department of Ginaecology and ObstetricsSchool of Medicine, University of ChileSantiagoChile
  5. 5.Clínica Santa MaríaSantiagoChile
  6. 6.School of Medicine and Clínica AlemanaUniversidad del DesarrolloSantiagoChile
  7. 7.Clínica DávilaSantiagoChile
  8. 8.Hospital San JoséSantiagoChile
  9. 9.Endocrinology and Reproductive Biology LaboratoryClinical Hospital University of Chile (HCUCH)SantiagoChile

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