Familial breast cancer

  • David E. Goldgar
  • Michael R. Stratton
  • Rosalind A. Eeles


Breast cancer has been recognized for over 100 years as having a familial component [1]. More recently, a number of epidemiological investigations have attempted to quantify the risks of breast cancer associated with a positive family history. Attempts have also been made to examine whether the pattern of related individuals with breast cancer are consistent with the effects of a single gene of large effect, shared environmental effects, many genes acting in an additive manner, or most likely, a combination of two or more of these effects. In addition to this statistical and observational evidence for the role of genes in the development of breast cancer, a number of specific genes have been identified as playing a role. Perhaps the most notable of these genes is BRCA1, which was identified through genetic linkage studies and localized to the long arm of chromosome 17 [2]. Because BRCA1 has been extensively studied, it is the subject of a separate chapter (Chapter 15) in this book. However, the BRCA1 gene accounts for, at most, half (and probably less) of all familial breast cancer. In this chapter, we will begin by examining the epidemiological evidence for familial risks in breast cancer, then discuss the results of statistical analyses of breast cancer families for the presence of major genetic effects, and describe specific genes other than BRCA1 which influence breast cancer risk. We will also present evidence that additional genes exist, as yet unmapped, which account for a substantial proportion of familial breast cancer.


Breast Cancer Ovarian Cancer Breast Cancer Risk Familial Risk Familial Breast Cancer 
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  1. 1.
    Broca, P.P. (1866) Traites des Tumeurs. Asselin, Paris, France.Google Scholar
  2. 2.
    Hall, J.M., Lee, M.K., Newman, B. et al. (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science, 250, 1684–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Cannon-Albright, L.A., Bishop, D.T., Goldgar, C. and Skolnick, M.H. (1991) Genetic predisposition to cancer, in Important Advances in Oncology, (eds V.T. DeVita Jr., S. Hellman and S.A. Rosenberg), J.B. Lippincott, Philadelphia, pp. 39–55.Google Scholar
  4. 4.
    Martynova, R.P. (1936) On the genetics of breast cancer in women. Proc. Maxim-Gorky Res. Inst., 4, 159–73.Google Scholar
  5. 5.
    Jacobsen, O. (1946) Heredity and Breast Cancer, H.K. Lewis, London.Google Scholar
  6. 6.
    Penrose, L.S., Mackenzie, J.H. and Karn, M.N. (1948) A genetical study of human mammary cancer. Ann. Eugenics, 14, 234–66.Google Scholar
  7. 7.
    Smithers, D.W. (1948) Family histories of 459 patients with cancer of the breast. Br. J. Cancer, 2, 163–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Woolf, C.M. (1955) Investigations on genetic aspects of carcinoma of the stomach and breast. University of California Publications in Public Health, 2, 265–73.Google Scholar
  9. 9.
    Anderson, V.E., Goodman, H.O. and Reed, S.C. (1958) Variables Related to Human Breast Cancer, University of Minnesota Press, Minneapolis.Google Scholar
  10. 10.
    Macklin, M.T. (1959) Comparison of the number of breast-cancer deaths observed in relatives of breast-cancer patients, and the number expected on the basis of mortality rates. J. Natl Cancer Inst., 22, 927–51.PubMedGoogle Scholar
  11. 11.
    Murphey, D.P. and Abbey, H. (1959) Cancer in Families. (A study of the relatives of 200 Breast Cancer Probands.) Harvard University Press, Cambridge.Google Scholar
  12. 12.
    Anderson, D.E. (1971) Some characteristics of familial breast cancer. Cancer, 28, 1500–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Anderson, D.E. (1972) A genetic study of human breast cancer. J. Natl Cancer Inst. 48, 1029–34.PubMedGoogle Scholar
  14. 14.
    Anderson, D.E. (1974) Genetic study of breast cancer: identification of a high risk group. Cancer, 34, 1090–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Anderson, D.E. (1976) Genetic predisposition to breast cancer. Rec. Res. Cancer Res., 57, 10–20.Google Scholar
  16. 16.
    Tulinius, H., Day, N.E. Sigvaldason, H. et al. (1980) A population-based study on familial aggregation of breast cancer in Iceland, taking some other risk factors into account, in Genetic and Environmental Factors in Experimental and Human Cancer, (eds H.V. Gelboin et al.), Japan Scientific Society Press, Japan, pp. 303–12.Google Scholar
  17. 17.
    Brinton, L.A., Hoover, R.N. and Fraumeni, J.F. (1982) Interaction of familial and hormonal risk factors for breast cancer. J. Natl Cancer Inst., 69, 817–22.PubMedGoogle Scholar
  18. 18.
    Sattin, R.W., Rubin, G.L., Webster, L.A. et al. (1985) Family history and the risk of breast cancer. JAMA, 253, 1908–13.PubMedCrossRefGoogle Scholar
  19. 19.
    Ottman, R., Pike, M.C., King, M-C, Casagrande, J.T. and Henderson, B.E. (1986) Familial breast cancer in a population based series. Am. J. Epidemiol, 123, 15–21.PubMedGoogle Scholar
  20. 20.
    Negri, E., La Vecchia, C, Bruzzi, P. et al. (1988) Risk factors for breast cancer: pooled results from three Italian case-control studies. Am. J. Epidemiol., 128, 1207–15.PubMedGoogle Scholar
  21. 21.
    Saftlas, A.F., Wolfe, J.N., Hoover, R.N. et al. (1989) Mammographic parenchymal patterns as indicators of breast cancer risk. Am. J. Epidemiol., 129, 518–26.PubMedGoogle Scholar
  22. 22.
    Carter, C.L., Jones, D.Y., Schatzkin, A. and Brinton, L.A. (1989) A prospective study of reproductive, familial and socioeconomic risk factors for breast cancer using NHANES I data. Public Health Rep., 104, 45–50.PubMedGoogle Scholar
  23. 23.
    Schildkraut, J.M., Risch, N. and Thompson, W.D. (1989) Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship. Am. J. Hum. Genet., 45, 521–9.PubMedGoogle Scholar
  24. 24.
    Mettlin, C, Croghan, I., Natarajan, N. and Lane, W. (1990) The association of age and familial risk in a case-control study of breast cancer. Am. J. Epidemiol., 131, 973–83.PubMedGoogle Scholar
  25. 25.
    Claus, E.B., Risch, N. and Thompson, W.D. (1990) Age of onset as an indicator of familial risk of breast cancer. Am. J. Epidemiol., 131, 961–72.PubMedGoogle Scholar
  26. 26.
    Houlston, R.S., McCarter, E., Parbhoo, S. et al. (1992) Family history and risk of breast cancer. J. Med. Genet., 29, 154–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Tulinius, H., Egilsson, V., Olafsdottir, G.H. and Sigvaldsson, H. (1992) Risk of prostate, ovarian and endometrial cancer among relatives of women with breast cancer. Br. Med. J., 305, 855–7.CrossRefGoogle Scholar
  28. 28.
    Slattery, M.L. and Kerber R.A. (1993) A comprehensive evaluation of family history and breast cancer risk. JAMA, 270, 1563–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Goldgar, D.E., Easton, D.F., Cannon-Albright, L.A. and Skolnick, M.H. (1994) Systematic population-based assessment of cancer risk in first degree relatives of cancer probands. J. Natl Cancer Inst., 86, 1600–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Casagrande, J.T., Hanisch, R., Pike, M.C. et al. (1988) A case-control study of male breast cancer. Cancer Res., 48, 1326–30.PubMedGoogle Scholar
  31. 31.
    Rosenblatt, K.A., Thomas, D.B., McTiernan, A. et al. (1991) Breast cancer in men: aspects of familial aggregation. J. Natl Cancer Inst., 83, 849–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Anderson, D.E. and Badzioch, M.D. (1992) Breast cancer risks in relatives of male breast cancer patients. J. Natl Cancer Inst., 84, 1114–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Claus, E.B., Risch, N. and Thompson, W.D. (1991) Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J. Hum. Genet. 48, 232–42.PubMedGoogle Scholar
  34. 34.
    Claus, E.B., Risch, N. and Thompson, W.D. (1993) Relationship between breast histopathology and family history of breast cancer. Cancer, 71, 147–53.PubMedCrossRefGoogle Scholar
  35. 35.
    Erdreich, L.S., Asal, N.R. and Hoge, A.F. (1980) Morphologic types of breast cancer: age, bilaterality, and family history. South. Med. J., 73, 28–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Lagios, M.D., Rose, M.E. and Margolin, F.R. (1980) Tubular carcinoma of the breast: association with multicentricity, bilaterality and family history. Am. J. Clin. Pathol., 73, 25–30.PubMedGoogle Scholar
  37. 37.
    Lagios, M.D. (1977) Multicentricity of breast carcinoma demonstrated by routine correlated serial subgross and radiographic examination. Cancer, 40, 1726–34.PubMedCrossRefGoogle Scholar
  38. 38.
    Lynch, H.T., Albano, W.A., Heieck, J.J. et al. (1984) Genetics, biomarkers, and control of breast cancer: a review. Cancer Genet. Cytogenet., 13, 43–92.PubMedCrossRefGoogle Scholar
  39. 39.
    Rosen, P.P., Lesser, M.L., Senie, R.T. and Kinne, D.W. (1982) Epidemiology of breast carcinoma. III. Relationship of family history to tumor type. Cancer, 50, 171–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Burki, N., Buser, M., Emmons, L.R. et al. (1990) Malignancies in families of women with medullary, tubular, and invasive ductal breast cancer. Eur. J. Cancer Clin. Oncol., 26, 295–303.CrossRefGoogle Scholar
  41. 41.
    Cannon, L., Bishop, D.T., Skolnick, M.H. et al. (1982) Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv., 1, 1–12.Google Scholar
  42. 42.
    Ford, D., Easton, D.F., Bishop, D.T., Narod, S.A., Goldgar D.E. and the BCLC (1994) Risks of cancer in BRCA1-mutation carriers. Lancet, 343, 692–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Thompson, W.D. and Schildkraut, J.M. (1991) Family history of gynaecological cancers: relationship to the incidence of breast cancer to age 55. Int. J. Epidemiol., 20, 595–602.PubMedCrossRefGoogle Scholar
  44. 44.
    Nelson, C.L., Sellers, T.A., Rich, S.S. et al. (1993) Familial clustering of colon, breast, uterine and ovarian cancers as assessed by family history. Genet. Epidemiol., 10, 235–44.PubMedCrossRefGoogle Scholar
  45. 45.
    Anderson, D.E. and Badzioch, M.D. (1993) Familial breast cancer risks: Effects of prostate and other cancers. Cancer, 72, 114–19.PubMedCrossRefGoogle Scholar
  46. 46.
    Parazzinni, F., Franceschi, S., Vecchia, C. and Fasoli, M. (1991) The epidemiology of ovarian cancer. Gynecol. Oncol., 43, 9–23.CrossRefGoogle Scholar
  47. 47.
    Lynch, H.T., Guirgis, H.A., Albert, S. et al. (1974) Familial association of carcinoma of the breast and ovary. Surgery, 138, 717–24.Google Scholar
  48. 48.
    Bishop, D.T., Albright, L.C., McClellan, T., Gardner, E.J. and Skolnick, M.H. (1988) Segregation and linkage analysis of nine Utah breast cancer pedigrees. Genet. Epidemiol., 5, 151–69.PubMedCrossRefGoogle Scholar
  49. 49.
    Bailey-Wilson, J.E., Cannon, L.A. and King, M.-C. (1986) Genetic analysis of human breast cancer: a synthesis of contributions to GAW IV. Genet. Epidemiol. (Suppl), 1, 15–35.CrossRefGoogle Scholar
  50. 50.
    King, M.-C., Cannon, L.A., Bailey-Wilson, J.E. et al. (1986) Genetic analysis of human breast cancer: literature review and description of family data in workshop. Genet. Epidemiol (Suppl), 1, 3–13.Google Scholar
  51. 51.
    Cannon, L.A., Bishop, D.T. and Skolnick, M.H. (1986) Segregation and linkage analysis of breast cancer in the Dutch and Utah families. Genet. Epidemiol., 3(1), 43–6.CrossRefGoogle Scholar
  52. 52.
    King, M.-C, Go, R.C.P., Elston, R.C. et al. (1980) Allele increasing susceptibility to human breast cancer may be linked to the glutamate-pyruvate transaminase locus. Science, 208, 406–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Skolnick, M.H., Thompson, E.A., Bishop, D.T. and Cannon, L.A. (1984) Possible linkage of a breast cancer susceptibility locus to the ABO locus: sensitivity of LOD scores to a single new recombinant observation. Genet. Epidemiol., 1, 363–73.PubMedCrossRefGoogle Scholar
  54. 54.
    Li, F.P. and Fraumeni, J.F. (1969) Soft tissue sarcomas, breast cancer and other neoplasms: a familial syndrome? Ann. Intern. Med., 71, 747–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Birch, J.M., Hartley, A.L., Tricker, K.J. et al. (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res., 54, 1298–304.PubMedGoogle Scholar
  56. 56.
    Borreson, A.L., Anderson, T.I., Garber, J. et al. (1992) Screening for germ line TP 53 mutations in breast cancer patients. Cancer Res., 52, 3234–6.Google Scholar
  57. 57.
    Sidransky, D., Tokino, T., Helzlsouer, K. et al. (1992) Inherited p53 mutations in breast cancer. Cancer Res., 52, 2984–6.PubMedGoogle Scholar
  58. 58.
    Swift, M., Reitnauer, P.J., Morrell, D. and Chase, C.L. (1991) Incidence of cancer in 161 families affected by ataxia telangiectasia. N. Engl. J. Med., 325, 1831–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Wagner, L.K. (1992) Correspondence: risk of breast cancer in ataxia-telangiectasia. N. Engl J. Med., 326, 1358–9.PubMedGoogle Scholar
  60. 60.
    Land, C.E. (1992) Correspondence: risk of breast cancer in ataxia-telangiectasia. N. Engl J. Med., 326, 1359–60.PubMedGoogle Scholar
  61. 61.
    Wooster, R., Ford, D., Mangion, J. et al. (1993) Absence of linkage to the ataxia-telangiectasia locus in familial breast cancer. Hum. Genet., 92, 91–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Fuqua, S.A., Chamness, G.C and McGuire, W.L. (1993) Estrogen receptor mutations in breast cancer. J. Cell Biochem., 51, 135–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Zuppan, P., Hall, J.M., Lee, M.K., Ponglikit-mongko, M. and King, M.-C. (1991) Possible linkage of the estrogen receptor gene to breast cancer in a family with late-onset disease. Am. J. Hum. Genet., 48, 1065–8.PubMedGoogle Scholar
  64. 64.
    Krontiris, T.G., Devlin, B., Karp, D.D., Robert, N.J. and Risch, N. (1993) An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. N. Engl. J. Med., 329, 517–23.PubMedCrossRefGoogle Scholar
  65. 65.
    Easton, D.F., Bishop, D.T., Ford, D. and Crockford, G.P. (1993) Genetic linkage analysis in familial breast and ovarian cancer — Results from 214 families. Am. J. Hum. Genet., 52, 678–701.PubMedGoogle Scholar
  66. 66.
    Narod, S.A., Ford D., Devilee P. et al. (1995) An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am. J. Hum. Genet. 56, 2254–64.Google Scholar
  67. 67.
    Stratton, M.R., Ford, D., Seal, S. et al. (1994) Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nature Genet., 7, 103–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Wooster, R., Neuhausen, S., Mangion, J. et al. (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science, 265, 2088–90.PubMedCrossRefGoogle Scholar
  69. 69.
    Wooster, R., Bignell, G., Swift, S. et al. (1995) Identification of the BRCA2 gene. Nature, 378, 789–92.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1996

Authors and Affiliations

  • David E. Goldgar
  • Michael R. Stratton
  • Rosalind A. Eeles

There are no affiliations available

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