Recent Advances in Breast Cancer Genetics

  • Boris Pasche
Part of the Cancer Treatment and Research book series (CTAR, volume 141)

Breast cancer is the second most common cancer among women and the second leading cause of cancer death in the US. In 2006, more than 214,000 new breast cancer cases were diagnosed. It is estimated that close to 50,000 women died of the same disease in 2006. Breast cancer develops in about 12% of women who live to age 90. A positive family history is reported by 15-20% of women with breast cancer. Studies of twins suggest that heritable factors accounts for 25 to 30% of all breast cancers. However, less than 7% of all breast cancers are associated with known inherited high penetrance gene mutations. The first two major susceptibility genes for breast cancer, BRCA1 and BRCA2, were identified in 1994 and 1995, respectively. Other tumor susceptibility genes such as TP53 are known to increase breast cancer risk to an even greater level than BRCA1 and BRCA2. Nonetheless, deleterious mutations of TP53 are rare and therefore accounts for a much smaller proportion of breast cancer cases.We will review recent developments in the search for additional breast cancer susceptibility genes, recommendations for genetic counseling referral as well as follow-up of BRCA- gene mutation carriers.


Breast Cancer Breast Cancer Risk BRCA2 Gene Contralateral Breast Cancer BRCA2 Mutation Carrier 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Abeliovich, D., L. Kaduri, I. Lerer, N. Weinberg, G. Amir, M. Sagi, J. Zlotogora, N. Heching, and T. Peretz. 1997. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 60:505–14.PubMedGoogle Scholar
  2. 2.
    Antoniou, A. P. D. Pharoah, S. Narod, H. A. Risch, J. E. Eyfjord, J. L. Hopper, N. Loman, H. Olsson, O. Johannsson, A. Borg, B. Pasini, P. Radice, S. Manoukian, D. M. Eccles, N. Tang, E. Olah, H. Anton-Culver, E. Warner, J. Lubinski, J. Gronwald, B. Gorski, H. Tulinius, S. Thorlacius, H. Eerola, H. Nevanlinna, K. Syrjakoski, O.P. Kallioniemi, D. Thompson, C. Evans, J. Peto, F. Lalloo, D. G. Evans, and D.F Easton. 2003. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:xxx–xxx.CrossRefGoogle Scholar
  3. 3.
    Baxter S. W., D. Y. Choong, D. M. Eccles, I. G. Campbell. 2002. Transforming Growth Factor beta Receptor 1 Polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 11: 211–14.PubMedGoogle Scholar
  4. 4.
    Berry D. A., E. S. J. Iversen, D. F. Gudbjartsson, E. H. Hiller, J. E. Garber, B. N. Peshkin, C. Lerman, P. Watson, H. T. Lynch, S. G Hilsenbeck, W. S. Rubinstein, K. S. Hughes, G. Parmigiani. 2002. BRCAPRO Validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20: 2701–12.PubMedCrossRefGoogle Scholar
  5. 5.
    Bond GL, W. Hu, E. E. Bond, H. Robins, S. G. Lutzker, N. C. Arva, J. Bargonetti, F. Bartel, H. Taubert, P. Wuerl, K. Onel, L. Yip, S. J. Hwang, L. C. Strong, G. Lozano, A. J. Levine. 2004. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119: 591–602.PubMedCrossRefGoogle Scholar
  6. 6.
    Claus E. B., N. Risch, W.D. Thompson. 1994. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73: 643–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Daly M.B., J. E. Axilbund, E. Bryant, S. Buys, C. Eng, S. Friedman, L. J. Esserman, C. D. Farrell, J. M. Ford, J. E. Garber, J. M. Jeter, W. Kohlmann, P. M. Lynch, P. K. Marcom, L. M. Nabell, K. Offit, R. U. Osarogiagbon, B. Pasche, G. Reiser, R Sutphen, J. N. Weitzel. 2006. Genetic/Familial high-risk assessment: breast and ovarian. J Natl Compr Canc Netw 4: 156–76.PubMedGoogle Scholar
  8. 8.
    Deng C. X. 2006. BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res 34: 1416–26.PubMedCrossRefGoogle Scholar
  9. 9.
    Evers B., J. Jonkers. 2006. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene 25: 5885–97.PubMedCrossRefGoogle Scholar
  10. 10.
    FitzGerald M. G., D. J. MacDonald, M. Krainer, I. Hoover, E. O’Neil, H. Unsal, S. Silva-Arrieto, D. M. Finkelstein, P. Beer-Romero, C. Englert, D. C. Sgroi, B. L. Smith, J. W. Younger, J. E. Garber, R. B. Duda, K. A. Mayzel, K. J. Isselbacher, S. H. Friend, D. A. Haber. 1996. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 334: 143–49.PubMedCrossRefGoogle Scholar
  11. 11.
    Frank T. S., A. M. Deffenbaugh, J. E. Reid, M. Hulick, B. E. Ward, B. Lingenfelter, K. L. Gumpper, T. Scholl, S. V. Tavtigian, D. R. Pruss, G. C. Critchfield. 2002. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10, 000 individuals. J Clin Oncol 20: 1480–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Genetic Testing in an Ethnically Diverse Cohort of High-Risk Women: A Comparative Analysis of BRCA1 and BRCA2 Mutations in American Families of European and African Ancestry by Nanda et al., JAMA 2005, 294: 1925–1933.Google Scholar
  13. 13.
    Hartmann L. C., T. A. Sellers, D. J. Schaid, T. S. Frank, C. L. Soderberg, D. L. Sitta, M. H. Frost, C. S. Grant, J. H. Donohue, J. E. Woods, S. K. McDonnell, C. W. Vockley, A Deffenbaugh, F. J. Couch, R. B. Jenkins. 2001. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93: 1633–37.PubMedCrossRefGoogle Scholar
  14. 14.
    Jemal A., R. Siegel, E. Ward, T. Murray, J. Xu, C. Smigal, M. J. Thun. 2006. Cancer statistics, 2006. Ca: a Cancer Journal for Clinicians 56: 106–30.CrossRefGoogle Scholar
  15. 15.
    Kaklamani V. G., L. Baddi, J. Liu, D. Rosman, S. Phukan, C. Bradley, C. Hegarty, B. McDaniel, A. Rademaker, C. Oddoux, H. Ostrer, L. S. Michel, H. Huang, Y. Chen, H. Ahsan, K. Offit, B. Pasche. 2005. Combined genetic assessment of transforming growth factor-{beta} signaling pathway variants may predict breast cancer risk. Cancer Res 65: 3454–61.PubMedGoogle Scholar
  16. 16.
    Kaklamani V.G, Hou N., Bian Y., Reich J., Offit K., Michel LS, Rubinstein W.S., Rademaker A., Pasche B 2003. TGFBR1*6A and Cancer risk: a meta-analysis of seven case-control studies. J Clin Oncol 21: 3236–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Kauff N. D., J. M. Satagopan, M. E. Robson, L. Scheuer, M. Hensley, C. A. Hudis, N. A. Ellis, J. Boyd, P. I. Borgen, R. R. Barakat, L. Norton, M. Castiel, K. Nafa, K. Offit. 2002. Risk-Reducing Salpingo-oophorectomy in Women with a BRCA1 or BRCA2 Mutation. N Engl J Med 346: 1609–15.PubMedCrossRefGoogle Scholar
  18. 18.
    King M. C., J. H. Marks, J. B. Mandell. 2003. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302: 643–46.PubMedCrossRefGoogle Scholar
  19. 19.
    Kriege M., C. T. M. Brekelmans, C. Boetes, P. E. Besnard, H. M. Zonderland, I. M. Obdeijn, R. A. Manoliu, T. Kok, H. Peterse, M. M. A. Tilanus-Linthorst, S. H. Muller, S. Meijer, J. C. Oosterwijk, L. V. A. M. Beex, R. A. E. M. Tollenaar, H. J. de Koning, E. J. T. Rutgers, J. G. M. Klijn, the Magnetic Resonance Imaging Screening Study Group. 2004. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351: 427–37.PubMedCrossRefGoogle Scholar
  20. 20.
    Lalloo F., J. Varley, D. Ellis, A. Moran, L. O’Dair, P. Pharoah, D. G. Evans. 2003. Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet 361: 1101–02.PubMedCrossRefGoogle Scholar
  21. 21.
    Lichtenstein P., N. V. Holm, P. K. Verkasalo, A. Iliadou, J. Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe, K. Hemminki. 2000. Environmental and heritable factors in the causation of cancer - Analyses of cohorts of twins from Sweden, Denmark, and Finland. N E J Med 343: 78–85.CrossRefGoogle Scholar
  22. 22.
    Limited Family Structure and BRCA Gene Mutation Status in Single Cases of Breast Cancer JAMA, June 20, 2007; 297: 2587–2595.Google Scholar
  23. 23.
    Meijers-Heijboer H., B. van Geel, W. L. J. van Putten, S. C. Henzen-Logmans, C. Seynaeve, M. B. E. Menke-Pluymers, C. C. M. Bartels, L. C. Verhoog, A. M. W. van den Ouweland, M. F. Niermeijer, C. T. M. Brekelmans, J. G. M. Klijn 2001. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N E J Med 345: 159–64.CrossRefGoogle Scholar
  24. 24.
    Metcalfe K., H. T. Lynch, P. Ghadirian, N. Tung, I. Olivotto, E. Warner, O. I. Olopade, A. Eisen, B. Weber, J. McLennan, P. Sun, W. D. Foulkes, S. A. Narod.2004. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22: 2328–2335.PubMedCrossRefGoogle Scholar
  25. 25.
    Miki Y., J. Swensen, D. Shattuck-Eidens, P. A. Futreal, K. Harshman, S. Tavtigian, Q. Liu, C. Cochran, L. M. Bennett, W. Ding,. 1994. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Muto M. G., D. W. Cramer, J. Tangir, R. Berkowitz, S. Mok. 1996. Frequency of the BRCA1 185delAG mutation among Jewish women with ovarian cancer and matched population controls. Cancer Res 56: 1250–52.PubMedGoogle Scholar
  27. 27.
    Narod S. A., J. S. Brunet, P. Ghadirian, M. Robson, K. Heimdal, S. L. Neuhausen, D. Stoppa-Lyonnet, C. Lerman, B. Pasini, R. P. De los, B. Weber, H. Lynch. 2000. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 356: 1876–81.PubMedCrossRefGoogle Scholar
  28. 28.
    Pasche B., P. Kolachana, K. Nafa, J. Satagopan, Y. G. Chen, R. S. Lo, D. Brener, D. Yang, L. Kirstein, C. Oddoux, H. Ostrer, P. Vineis, L. Varesco, S. Jhanwar, L. Luzzatto, J. Massague, K. Offit. 1999 T beta R-I6A is a candidate tumor susceptibility allele. Cancer Res 59: 5678–82.PubMedGoogle Scholar
  29. 29.
    Pasche B., Y. Luo, P. H. Rao, S. D. Nimer, E. Dmitrovsky, P. Caron, L. Luzzatto, K. Offit, C. Cordon-Cardo, B. Renault, J. M. Satagopan, V. V. Murty, J. Massague. 1998. Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract. Cancer Res 58: 2727–32.PubMedGoogle Scholar
  30. 30.
    Pasche B., T. J. Knobloch, Y. Bian, J. Liu, S. Phukan, D. Rosman, V. Kaklamani, L. Baddi, F. S. Siddiqui, W. Frankel, T. W. Prior, D. E. Schuller, A. Agrawal, J. Lang, M. E. Dolan, E. E. Vokes, W. S. Lane, C. C. Huang, T. Caldes, A. Di Cristofano, H. Hampel, I. Nilsson, G. von Heijne, R. Fodde, V. V. V. S. Murty, A. de la Chapelle, C. M. Weghorst. 2005. Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA294: 1634–46.PubMedCrossRefGoogle Scholar
  31. 31.
    Pharoah P. D., A. Antoniou, M. Bobrow, R. L. Zimmern, D. F. Easton, B. A. Ponder. 2002. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31: 33–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Phillips K. A., M. A. Jenkins, G. J. Lindeman, S. A. McLachlan, J. M. McKinley, P. C. Weideman, J. L. Hopper, M. L. Friedlander. 2006. Risk-reducing Surgery, Screening and Chemoprevention practices of Brcai and BRCA2 mutation carriers: A prospective cohort study, Clinical Genetics 70: 198–206.PubMedCrossRefGoogle Scholar
  33. 33.
    Pierce D. F., Jr., A. E. Gorska, A. Chytil, K. S. Meise, D. L. Page, R. J. Coffey, Jr., H. L. Moses. 1995. Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc Natl Acad Sci U S A 92: 4254–58.PubMedCrossRefGoogle Scholar
  34. 34.
    Rebbeck T. R., T. Friebel, H. T. Lynch, S. L. Neuhausen, L. ‘t Veer, J. E. Garber, G. R. Evans, S. A. Narod, C. Isaacs, E. Matloff, M. B. Daly, O. I. Olopade, B. L. Weber. 2004. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol 22: 1055–62.PubMedCrossRefGoogle Scholar
  35. 35.
    Rebbeck T. R., H. T. Lynch, S. L. Neuhausen, S. A. Narod, L. van’t Veer, J. E. Garber, G. Evans, C. Isaacs, M. B. Daly, E. Matloff, O. I. Olopade, B. L. Weber, the Prevention and Observation of Surgical End Points Study Group. 2002. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346: 1616–22.PubMedCrossRefGoogle Scholar
  36. 36.
    ShattuckEidens D., M. Mcclure, J. Simard, F. Labrie, S. Narod, F. Couch, K. Hoskins, B. Weber, L. Castilla, M. Erdos, L. Brody, L. Friedman, E. Ostermeyer, C. Szabo, M. C. King, S. Jhanwar, K. Offit, L. Norton, T. Gilewski, M. Lubin, M. Osborne, D. Black, M. Boyd, M. Steel, S. Ingles, R. Haile, A. Lindblom, H. Olsson, A. Borg, D. T. Bishop, E. Solomon, P. Radice, G. Spatti, S. Gayther, B. Ponder, W. Warren, M. Stratton, Q. Y. Liu, F. Fujimura, C. Lewis, M. H. Skolnick, D. E. Goldgar. 1995. A collaborative survey of 80 mutations in the brca1 breast-cancer and ovarian-cancer susceptibility gene - implications for presymptomatic testing and screening. JAMA 273: 535–41.CrossRefGoogle Scholar
  37. 37.
    Struewing J. P., P. Hartge, S. Wacholder, S. M. Baker, M. Berlin, M. McAdams, M. M. Timmerman, L. C. Brody, M. A. Tucker. 1997. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews [see comments]. N E J Med 336: 1401–08.CrossRefGoogle Scholar
  38. 38.
    Walsh T., S. Casadei, K. H. Coats, E. Swisher, S. M. Stray, J. Higgins, K. C. Roach, J. Mandell, M. K. Lee, S. Ciernikova, L. Foretova, P. Soucek, M. C. King. 2006. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295: 1379–88.PubMedCrossRefGoogle Scholar
  39. 39.
    Warner E., W. Foulkes, P. Goodwin, W. Meschino, J. Blondal, C. Paterson, H. Ozcelik, P. Goss, D. lingham-Hawkins, N. Hamel, P. L. Di, V. Contiga, C. Serruya, M. Klein, R. Moslehi, J. Honeyford, A. Liede, G. Glendon, J. S. Brunet, S. Narod. 1999. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91: 1241–47.PubMedCrossRefGoogle Scholar
  40. 40.
    Wideroff L., S. T. Vadaparampil, N. Breen, R. T. Croyle, A. N. Freedman. 2003. Awareness of genetic testing for increased cancer risk in the year 2000 National Health Interview Survey. Community Genet 6: 147–56.PubMedCrossRefGoogle Scholar
  41. 41.
    Wooster R., G. Bignell, J. Lancaster, S. Swift, S. Seal, J. Mangion, N. Collins, S. Gregory, C. Gumbs, G. Micklem, R. Barfoot, R. Hamoudi, S. Patel, C. Rice, P. Biggs, Y. Hashim, A. Smith, F. Connor, A. Arason, J. Gudmundsson, D. Ficenec, D. Kelsell, D. Ford, P. Tonin, D. T. Bishop, N. K. Spurr, B. A. J. Ponder, R. Eeles, J. Peto, P. Devilee, C. Cornelisse, H. Lynch, S. Narod, G. Lenoir, V. Egilsson, R. B. Barkadottir, D. F. Easton, D. R. Bentley, P. A. Futreal, A. Ashworth, M. R. Stratton. 1995. Identification of the breast-cancer susceptibility gene Brca2. Nature 378: 789–92.PubMedCrossRefGoogle Scholar
  42. 42.
    Yoshida K., Y. Miki. 2004. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 95: 866–71.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang HT, J. Zhao, S. Y. Zheng, X. F. Chen. 2005. Is TGFBR1*6A really associated with increased risk of cancer? J Clin Oncol 23: 7743–44.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Boris Pasche
    • 1
  1. 1.Robert H. Lurie Comprehensive Cancer CenterNorthwestern University School of MedicineChicagoUSA

Personalised recommendations