A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability (original) (raw)

Nature Genetics volume 26, pages 362–364 (2000)Cite this article

Abstract

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair1,2. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence3,4. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07–1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.

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Acknowledgements

We thank K. Redman, J. Gregory and J. Lipscombe for sample management in series 1 and 2; M.R. Stratton and J. Peto for access to the DNA samples in series 3; the NCCGP team at Westlakes Research Institute for the preparation of the newborn DNA samples, and at Newcastle University for providing the data; the physicians of the Children's and Women's Health Centre of British Columbia for the spontaneous abortion specimens; J. MacKay for facilitating the collaboration with Kuopio; and A. Trainer for helpful support. This work was funded by The Cancer Research Campaign (CRC) and Kuopio University Hospital EVO grant. Strangeways Research Laboratory has received a UK National Lottery Award. B.A.J.P. is a Gibb Fellow of the CRC.

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Author notes

  1. Catherine S. Healey and Alison M. Dunning: These authors contributed equally to this work.

Authors and Affiliations

  1. CRC Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
    Catherine S. Healey, Alison M. Dunning, Paul D.P. Pharoah & Bruce A.J. Ponder
  2. CRC Genetic Epidemiology Group, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
    M. Dawn Teare & Douglas F. Easton
  3. EPIC, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
    Robert N. Luben
  4. Genetics Unit, Westlakes Research Institute, Cumbria, UK
    Diana Chase
  5. Institute of Child Health, University of Newcastle, Royal Victoria Infirmary, Newcastle Upon Tyne, UK
    Louise Parker
  6. Human Genetics Unit, School of Biochemistry and Genetics, University of Newcastle, Newcastle Upon Tyne, UK
    John Burn
  7. Abteilung Epidemiologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany
    Jenny Chang-Claude
  8. Department of Clinical Genetics, Kuopio University Hospital, Kuopio, Finland
    Arto Mannermaa
  9. Department of Oncology and Radiotherapy, Kuopio University and Kuopio University Hospital, Kuopio, Finland
    Vesa Kataja
  10. Department of Pathology and Laboratory Medicine, Children's and Women's Health Centre of British Columbia, Vancouver BC, Canada
    David G. Huntsman

Authors

  1. Catherine S. Healey
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  2. Alison M. Dunning
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  3. M. Dawn Teare
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  4. Diana Chase
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  5. Louise Parker
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  6. John Burn
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  7. Jenny Chang-Claude
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  8. Arto Mannermaa
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  9. Vesa Kataja
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  10. David G. Huntsman
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  11. Paul D.P. Pharoah
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  12. Robert N. Luben
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  13. Douglas F. Easton
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  14. Bruce A.J. Ponder
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Corresponding author

Correspondence toCatherine S. Healey.

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Healey, C., Dunning, A., Dawn Teare, M. et al. A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.Nat Genet 26, 362–364 (2000). https://doi.org/10.1038/81691

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