A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability (original) (raw)
- Letter
- Published: November 2000
- Alison M. Dunning1 na1,
- M. Dawn Teare2,
- Diana Chase4,
- Louise Parker5,
- John Burn6,
- Jenny Chang-Claude7,
- Arto Mannermaa8,
- Vesa Kataja9,
- David G. Huntsman10,
- Paul D.P. Pharoah1,
- Robert N. Luben3,
- Douglas F. Easton2 &
- …
- Bruce A.J. Ponder1
Nature Genetics volume 26, pages 362–364 (2000)Cite this article
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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
- Catherine S. Healey and Alison M. Dunning: These authors contributed equally to this work.
Authors and Affiliations
- 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 - CRC Genetic Epidemiology Group, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
M. Dawn Teare & Douglas F. Easton - EPIC, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
Robert N. Luben - Genetics Unit, Westlakes Research Institute, Cumbria, UK
Diana Chase - Institute of Child Health, University of Newcastle, Royal Victoria Infirmary, Newcastle Upon Tyne, UK
Louise Parker - Human Genetics Unit, School of Biochemistry and Genetics, University of Newcastle, Newcastle Upon Tyne, UK
John Burn - Abteilung Epidemiologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany
Jenny Chang-Claude - Department of Clinical Genetics, Kuopio University Hospital, Kuopio, Finland
Arto Mannermaa - Department of Oncology and Radiotherapy, Kuopio University and Kuopio University Hospital, Kuopio, Finland
Vesa Kataja - Department of Pathology and Laboratory Medicine, Children's and Women's Health Centre of British Columbia, Vancouver BC, Canada
David G. Huntsman
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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
- Received: 20 June 2000
- Accepted: 26 September 2000
- Issue Date: November 2000
- DOI: https://doi.org/10.1038/81691