Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The emerging landscape of breast cancer susceptibility

Abstract

The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alleles and common low-penetrance alleles. The contribution of each component to breast cancer predisposition is still to be fully explored, as are the phenotypic characteristics of the cancers associated with them, the ways in which they interact, much of their biology and their clinical utility. These recent advances herald a new chapter in the exploration of susceptibility to breast cancer and are likely to provide insights relevant to other common, heterogeneous diseases.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50,302 women with breast cancer and 96,973 women without the disease. Lancet 360, 187–195 (2002).

  2. Peto, J. & Mack, T.M. High constant incidence in twins and other relatives of women with breast cancer. Nat. Genet. 26, 411–414 (2000).

    CAS  Article  Google Scholar 

  3. Hall, J.M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  7. Thompson, D. & Easton, D.F. Cancer incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 94, 1358–1365 (2002).

    CAS  Article  Google Scholar 

  8. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 91, 1310–1316 (1999).

  9. Anglian Breast Cancer Study Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br. J. Cancer 83, 1301–1308 (2000).

  10. Peto, J. et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J. Natl. Cancer Inst. 91, 943–949 (1999).

    CAS  Article  Google Scholar 

  11. Gudmundsdottir, K. & Ashworth, A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25, 5864–5874 (2006).

    CAS  Article  Google Scholar 

  12. Thompson, D. & Easton, D. The genetic epidemiology of breast cancer genes. J. Mammary Gland Biol. Neoplasia 9, 221–236 (2004).

    Article  Google Scholar 

  13. Antoniou, A.C. & Easton, D.F. Models of genetic susceptibility to breast cancer. Oncogene 25, 5898–5905 (2006).

    CAS  Article  Google Scholar 

  14. Smith, P. et al. A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosom. Cancer 45, 646–655 (2006).

    CAS  Article  Google Scholar 

  15. Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 39, 165–167 (2007).

    CAS  Article  Google Scholar 

  16. Meijers-Heijboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet. 31, 55–59 (2002).

    CAS  Article  Google Scholar 

  17. Renwick, A. et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 38, 873–875 (2006).

    CAS  Article  Google Scholar 

  18. Seal, S. et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 38, 1239–1241 (2006).

    CAS  Article  Google Scholar 

  19. Erkko, H. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007).

    CAS  Article  Google Scholar 

  20. Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    CAS  Article  Google Scholar 

  21. Hunter, D.J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874 (2007).

    CAS  Article  Google Scholar 

  22. Stacey, S.N. et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 39, 865–869 (2007).

    CAS  Article  Google Scholar 

  23. Ahn, J., Urist, M. & Prives, C. The Chk2 protein kinase. DNA Repair (Amst.) 3, 1039–1047 (2004).

    CAS  Article  Google Scholar 

  24. Shiloh, Y. The ATM-mediated DNA-damage response: taking shape. Trends Biochem. Sci. 31, 402–410 (2006).

    CAS  Article  Google Scholar 

  25. Peng, M., Litman, R., Jin, Z., Fong, G. & Cantor, S.B. BACH1 is a DNA repair protein supporting BRCA1 damage response. Oncogene 25, 2245–2253 (2006).

    CAS  Article  Google Scholar 

  26. Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).

    CAS  Article  Google Scholar 

  27. CHEK2 Breast Cancer Case-Control Consortium. CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am. J. Hum. Genet. 74, 1175–1182 (2004).

  28. Vahteristo, P. et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am. J. Hum. Genet. 71, 432–438 (2002).

    CAS  Article  Google Scholar 

  29. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).

    CAS  Article  Google Scholar 

  30. Thompson, D. et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J. Natl. Cancer Inst. 97, 813–822 (2005).

    CAS  Article  Google Scholar 

  31. Howlett, N.G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002).

    CAS  Article  Google Scholar 

  32. Reid, S. et al. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J. Med. Genet. 42, 147–151 (2005).

    CAS  Article  Google Scholar 

  33. Levitus, M. et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat. Genet. 37, 934–935 (2005).

    CAS  Article  Google Scholar 

  34. Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

    CAS  Article  Google Scholar 

  35. Xia, B. et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat. Genet. 39, 159–161 (2007).

    CAS  Article  Google Scholar 

  36. Levran, O. et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat. Genet. 37, 931–933 (2005).

    CAS  Article  Google Scholar 

  37. Seal, S. et al. Evaluation of Fanconi anemia genes in familial breast cancer predisposition. Cancer Res. 63, 8596–8599 (2003).

    CAS  PubMed  Google Scholar 

  38. van Puijenbroek, M. et al. Homozygosity for a CHEK2*1100delC mutation identified in familial colorectal cancer does not lead to a severe clinical phenotype. J. Pathol. 206, 198–204 (2005).

    CAS  Article  Google Scholar 

  39. Breast Cancer Association Consortium. Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J. Natl. Cancer Inst. 98, 1382–1396 (2006).

  40. Cox, A. et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat. Genet. 39, 352–358 (2007).

    CAS  Article  Google Scholar 

  41. Amundadottir, L.T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).

    CAS  Article  Google Scholar 

  42. Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).

    CAS  Article  Google Scholar 

  43. Haiman, C.A. et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Genet. 39, 638–644 (2007).

    CAS  Article  Google Scholar 

  44. Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).

    CAS  Article  Google Scholar 

  45. Haiman, C.A. et al. A common genetic risk factor for colorectal and prostate cancer. Nat. Genet. 39, 954–956 (2007).

    CAS  Article  Google Scholar 

  46. Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).

    CAS  Article  Google Scholar 

  47. Zanke, B.W. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat. Genet. 39, 989–994 (2007).

    CAS  Article  Google Scholar 

  48. Pollock, P.M. et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26, 7158–7162 (2007).

    CAS  Article  Google Scholar 

  49. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    CAS  Article  Google Scholar 

  50. Honrado, E., Benitez, J. & Palacios, J. Histopathology of BRCA1- and BRCA2-associated breast cancer. Crit. Rev. Oncol. Hematol. 59, 27–39 (2006).

    Article  Google Scholar 

  51. Heikkinen, K. et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis 27, 1593–1599 (2006).

    CAS  Article  Google Scholar 

  52. Tommiska, J. et al. Evaluation of RAD50 in familial breast cancer predisposition. Int. J. Cancer 118, 2911–2916 (2006).

    CAS  Article  Google Scholar 

  53. Pharoah, P.D. et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat. Genet. 31, 33–36 (2002).

    CAS  Article  Google Scholar 

  54. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    CAS  Article  Google Scholar 

  55. Domchek, S.M. & Weber, B.L. Clinical management of BRCA1 and BRCA2 mutation carriers. Oncogene 25, 5825–5831 (2006).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We are grateful to C. Turnbull and R. Scott for their critical reading of the manuscript and helpful comments.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stratton, M., Rahman, N. The emerging landscape of breast cancer susceptibility. Nat Genet 40, 17–22 (2008). https://doi.org/10.1038/ng.2007.53

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2007.53

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing