Cancer Causes & Control

, Volume 21, Issue 5, pp 689–696

Birth weight, breast cancer susceptibility loci, and breast cancer risk

  • Rulla M. Tamimi
  • Pagona Lagiou
  • Kamila Czene
  • Jianjun Liu
  • Anders Ekbom
  • Chung-Cheng Hsieh
  • Hans-Olov Adami
  • Dimitrios Trichopoulos
  • Per Hall
Original paper



There is considerable evidence that birth weight is positively associated with breast cancer risk, and seven single-nucleotide polymorphisms (SNPs) have been conclusively associated with this risk. We have hypothesized that breast cancer susceptibility loci may have a greater influence on breast cancer risk among women with higher birth weight, who are expected to have a larger pool of mammary stem cells that are susceptible to malignant transformation.

Patients and methods

In the context of a nationwide, population-based case–control study in Sweden, we retrieved recorded birth weight for 693 breast cancer cases and 747 control women who were also genotyped for most or all of the seven recently documented breast cancer susceptibility SNPs: rs2981582, rs12443621, rs8051542, rs3803662, rs889312, rs13281615, and rs3817198.


We grouped heterozygotes with homozygotes for the wild-type allele, and we found a marginally significant interaction (p~0.07) between birth weight and rs2981582 (FGFR2), the genotype repeatedly identified as the top hit in genome-wide association studies. There were similar, though not significant, patterns for the other six SNPs.


Although our findings require confirmation, we found suggestive evidence that genetic susceptibility modifies the positive association of birth weight with breast cancer.


Allele Birth weight Breast cancer Gene Genotype Polymorphism 


  1. 1.
    Hankinson S, Tamimi R (2008) Hunter D. Breast cancer. In: Adami HO, Hunter D, Trichopoulos D (eds) Textbook of cancer epidemiology, 2nd edn. Oxford University Press, New York, pp 403–445Google Scholar
  2. 2.
    Lichtenstein P, Holm NV, Verkasalo PK et al (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85CrossRefPubMedGoogle Scholar
  3. 3.
    Lux MP, Fasching PA, Beckmann MW (2006) Hereditary breast and ovarian cancer: review and future perspectives. J Mol Med 84:16–28CrossRefPubMedGoogle Scholar
  4. 4.
    Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358:2796–2803CrossRefPubMedGoogle Scholar
  5. 5.
    Pharoah PD, Antoniou A, Bobrow M et al (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36CrossRefPubMedGoogle Scholar
  6. 6.
    Ponder BA, Antoniou A, Dunning A et al (2005) Polygenic inherited predisposition to breast cancer. Cold Spring Harb Symp Quant Biol 70:35–41CrossRefPubMedGoogle Scholar
  7. 7.
    Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108CrossRefPubMedGoogle Scholar
  8. 8.
    Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093CrossRefPubMedGoogle Scholar
  9. 9.
    Hunter DJ, Kraft P, Jacobs KB et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870–874CrossRefPubMedGoogle Scholar
  10. 10.
    Stacey SN, Manolescu A, Sulem P et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869CrossRefPubMedGoogle Scholar
  11. 11.
    Trichopoulos D (1990) Hypothesis: does breast cancer originate in utero? Lancet 335:939–940CrossRefPubMedGoogle Scholar
  12. 12.
    Michels KB, Xue F (2006) Role of birthweight in the etiology of breast cancer. Int J Cancer 119:2007–2025CrossRefPubMedGoogle Scholar
  13. 13.
    Lagiou P (2007) Intrauterine factors and breast cancer risk. Lancet Oncol 8:1047–1048CrossRefPubMedGoogle Scholar
  14. 14.
    Xue F, Michels KB (2007) Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence. Lancet Oncol 8:1088–1100CrossRefPubMedGoogle Scholar
  15. 15.
    dos Santos Silva I, De Stavola B, McCormack V (2008) Collaborative group on pre-natal risk factors and subsequent risk of breast cancer. Birth size and breast cancer risk: re-analysis of individual participant data from 32 studies. PLoS Med 5:e193CrossRefGoogle Scholar
  16. 16.
    Park SK, Kang D, McGlynn KA et al (2008) Intrauterine environments and breast cancer risk: meta-analysis and systematic review. Breast Cancer Res 10:R8CrossRefPubMedGoogle Scholar
  17. 17.
    Adami H-O, Persson I, Ekbom A et al (1995) The aetiology and pathogenesis of human breast cancer. Mutat Res 333:29–35PubMedGoogle Scholar
  18. 18.
    Trichopoulos D, Lagiou P, Adami HO (2005) Towards an integrated model for breast cancer etiology: the crucial role of the number of mammary tissue-specific stem cells. Breast Cancer Res 7:13–17CrossRefPubMedGoogle Scholar
  19. 19.
    Strohsnitter WC, Savarese TM, Low HP et al (2008) Correlation of umbilical cord blood haematopoietic stem and progenitor cell levels with birth weight: implications for a prenatal influence on cancer risk. Br J Cancer 98:660–663CrossRefPubMedGoogle Scholar
  20. 20.
    Magnusson C, Baron J, Persson I et al (1998) Body size in different periods of life and breast cancer risk in post-menopausal women. Int J Cancer 76:29–34CrossRefPubMedGoogle Scholar
  21. 21.
    Magnusson CM, Persson IR, Baron JA et al (1999) The role of reproductive factors and use of oral contraceptives in the aetiology of breast cancer in women aged 50 to 74 years. Int J Cancer 80:231–236CrossRefPubMedGoogle Scholar
  22. 22.
    Magnusson C, Baron JA, Correia N et al (1999) Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer 81:339–344CrossRefPubMedGoogle Scholar
  23. 23.
    Liang J, Chen P, Hu Z et al (2008) Genetic variants in fibroblast growth factor receptor 2 (FGFR2) contribute to susceptibility of breast cancer in Chinese women. Carcinogenesis 29:2341–2346CrossRefPubMedGoogle Scholar
  24. 24.
    Gold B, Kirchhoff T, Stefanov S et al (2008) Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105:4340–4345CrossRefPubMedGoogle Scholar
  25. 25.
    Udler MS, Meyer KB, Pooley KA et al (2009) FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. Hum Mol Genet 18:1692–1703CrossRefPubMedGoogle Scholar
  26. 26.
    Penault-Llorca F, Bertucci F, Adélaïde J et al (1995) Expression of FGF and FGF receptor genes in human breast cancer. Int J Cancer 61:170–176CrossRefPubMedGoogle Scholar
  27. 27.
    Theodorou V, Kimm MA, Boer M et al (2007) MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer. Nat Genet 39:759–769CrossRefPubMedGoogle Scholar
  28. 28.
    Katoh M (2008) Cancer genomics and genetics of FGFR2 (Review). Int J Oncol 33:233–237PubMedGoogle Scholar
  29. 29.
    Ahmed S, Thomas G, Ghoussaini M et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41:585–590CrossRefPubMedGoogle Scholar
  30. 30.
    Thomas G, Jacobs KB, Kraft P 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 41:579–584CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Rulla M. Tamimi
    • 1
    • 2
  • Pagona Lagiou
    • 1
    • 3
  • Kamila Czene
    • 4
  • Jianjun Liu
    • 5
  • Anders Ekbom
    • 6
  • Chung-Cheng Hsieh
    • 1
    • 7
  • Hans-Olov Adami
    • 1
    • 4
  • Dimitrios Trichopoulos
    • 1
    • 4
  • Per Hall
    • 4
  1. 1.Department of EpidemiologyHarvard School of Public HealthBostonUSA
  2. 2.Channing LaboratoryHarvard Medical SchoolBostonUSA
  3. 3.Department of Hygiene, Epidemiology and Medical Statistics, School of MedicineUniversity of AthensAthensGreece
  4. 4.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
  5. 5.Population GeneticsGenome Institute of SingaporeSingaporeSingapore
  6. 6.Clinical Epidemiology Unit, Department of MedicineKarolinska Institutet/Karolinska University HospitalStockholmSweden
  7. 7.Division of Biostatistics and Epidemiology, UMass Cancer CenterUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations