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Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene

Nature Genetics volume 15, pages 103–105 (1997)Cite this article

Abstract

The breast cancer susceptibility gene BRCA2 on chromosome 13q12–13 has recently been identified1. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer2–4. Germline mutations of a second cancer susceptibility gene BRCA1 (ref. 5), are associated with a strong predisposition to ovarian cancer as well as female breast cancer6. Recent studies have suggested that the phenotype in BRCA1 families with respect to the ratio of breast to ovarian cancer varies with the location of the BRCA1 mutation7,8. To determine whether germline mutations in BRCA2 are associated with a similar variation in phenotypic risk, we have analysed the distribution of mutations in 25 families with multiple cases of breast and/or ovarian cancer ascertained in the United Kingdom and Eire. These mutations all lead to premature truncation of BRCA2 as a result of frameshift deletions/insertions or nonsense mutations. Analysis of the mutation distribution along the length of the gene indicates a significant genotype-phenotype correlation. Truncating mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in a region of approximately 3.3 kb in exon 11 (P = 0.0004). Published data on mutations in 45 other 0/?CA2-linked families provide support for this correlation.

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References

  1. Wooster, R. et al. Identification of the breast-cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).

    Article  CAS  Google Scholar 

  2. Wooster, R. et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265, 2088–2090 (1994).

    Article  CAS  Google Scholar 

  3. Thorlacius, S. et al. A single BRCA2 mutation in male and female breast-cancer families from Iceland with varied cancer phenotypes. Nature Genet. 13, 117–119 (1996).

    Article  CAS  Google Scholar 

  4. Phelan, C.M. et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast-cancer families. Nature Genet. 13, 120–122 (1996).

    Article  CAS  Google Scholar 

  5. Miki, Y. et al. A strong candidate for the breast and ovarian-cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    Article  CAS  Google Scholar 

  6. Easton, D.F., Bishop, D.T., Ford, D., Crockford, G.P. & the Breast Cancer Linkage Consortium. Genetic linkage analysis in familial breast and ovarian cancer. Am. J. Hum. Genet. 52, 718–722 (1993).

    Google Scholar 

  7. Gayther, S.A. et al. Germline mutations of the BRCA1 gene in breast and ovarian-cancer families provide evidence for a genotype-phenotype correlation. Nature Genet. 11, 428–433 (1995).

    Article  CAS  Google Scholar 

  8. Holt, J.T. et al. Growth-retardation and tumor-inhibition by BRCA1. Nature Genet 12, 298–302(1996).

    Article  CAS  Google Scholar 

  9. Gayther, S.A. et al. Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis. Am. J. Hum. Genet. 58, 451–456 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Tavtigian, S.V. et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nature Genet. 12, 333–337 (1996).

    Article  CAS  Google Scholar 

  11. Mazoyer, S. et al. A polymorphic stop codon in BRCA2. Nature Genet. 14, 253–254 (1996).

    Article  CAS  Google Scholar 

  12. Couch, F.J. et al. BRCA2 germline mutations in male breast-cancer cases and breast-cancer families. Nature Genet. 13, 123–125 (1996).

    Article  CAS  Google Scholar 

  13. Neuhausen, S. et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast-cancer. Nature Genet. 13, 126–128 (1996).

    Article  CAS  Google Scholar 

  14. Nagase, H. et al. Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res. 52, 4055–4057 (1992).

    CAS  PubMed  Google Scholar 

  15. Gayther, S.A. et al. Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli. Hum. Mol. Genet. 3, 53–56 (1994).

    Article  CAS  Google Scholar 

  16. Spirio, L. et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75, 951–957 (1993).

    Article  CAS  Google Scholar 

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Author notes

  1. Simon A. Gayther and Jonathon Mangion: S.A. G. & J.M. contributed equally to the study.

Authors and Affiliations

  1. CRC Human Cancer Genetics Research Group, Addenbrooke's Hospital, Box 238, Hills Road, Cambridge, CB22QQ, UK

    Simon A. Gayther, Paul Russell & Bruce A.J. Ponder

  2. Section of Molecular Carcinogenesis, Institute of Cancer Research, Haddow Laboratories, 15 CotswoldRoad, Button, Surrey, SM25NG, UK

    Jonathon Mangion, Sheila Seal, Rita Barfoot & Michael R. Stratton

  3. CRC Genetic Epidemiology Group, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge, CB2 2SR, UK

    Douglas Easton

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  1. Simon A. Gayther
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  7. Michael R. Stratton
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  8. Douglas Easton
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Gayther, S., Mangion, J., Russell, P. et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15, 103–105 (1997). https://doi.org/10.1038/ng0197-103

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