Skip to main content

Advertisement

SpringerLink
Log in

Inherited Mutations in Breast Cancer Genes—Risk and Response

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Germ-line mutations in BRCA1 and BRCA2 confer a high risk of developing breast cancer. They account, however, for only 40% of strongly familial breast cancer cases. Intensive genome-wide searches for other highly-penetrant BRCA genes that, individually account for a sizeable fraction of the remaining heritability has not identified any plausible candidates. The “missing heritability” is thought to be due to cumulative effects of susceptibility alleles associated with low to moderate penetrance, in accordance with a polygenic model of inheritance. In addition, a large number of individually very rare, highly penetrant variants could account for part of the gap. Meanwhile, an understanding of the function of BRCA1 and BRCA2 in the DNA damage response pathway has lead to the identification of a number of breast cancer susceptibility genes including PALB2, CHEK2, ATM and BRIP1, all of which interact directly or indirectly with BRCA1 or BRCA2. Knowledge of how BRCA1 and BRCA2 maintain genomic integrity has also led the development of novel targeted therapies. Here we summarize the recent advances made in the understanding of the functions of these two genes, as well as the risks and responses associated with mutations in these and other breast cancer susceptibility genes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1

Similar content being viewed by others

Abbreviations

ATM:

Ataxia telangiectasia mutated

BRCA1:

Breast cancer susceptibility gene 1

BRCA2:

Breast cancer susceptibility gene 2

BRIP1:

BRCA1-interacting protein 1

CtBP:

C terminal binding protein

DSB:

Double strand break

ER:

Estrogen receptor

GWAS:

Genome-wide association study

HER2:

Human epidermal growth factor receptor

HR:

Homologous repair

MRN:

Mre11–Rad50–Nbs1

OR:

Odds ratio

PALB2:

Partner and localizer of BRCA2

PARP:

Poly (ADP-ribose) polymerase

pCR:

Pathologic complete response

PR:

Progesterone receptor

RING:

Really interesting new gene

SNP:

Single nucleotide polymorphism

SUMO:

Small ubiquitin-like modifier

TNBC:

Triple negative breast cancer

References

  1. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004;4(9):665–76.

    PubMed  CAS  Google Scholar 

  2. Ford D et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998;62(3):676–89.

    PubMed  CAS  Google Scholar 

  3. Smith P et al. A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosom Cancer. 2006;45(7):646–55.

    PubMed  CAS  Google Scholar 

  4. Pharoah PDP et al. Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med. 2008;358(26):2796–803.

    PubMed  CAS  Google Scholar 

  5. Manolio TA et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53.

    PubMed  CAS  Google Scholar 

  6. Huen MS, Sy SM, Chen J. BRCA1 and its toolbox for the maintenance of genome integrity. Nat Rev Mol Cell Biol. 2010;11(2):138–48.

    PubMed  CAS  Google Scholar 

  7. Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 2010;11(3):196–207.

    PubMed  CAS  Google Scholar 

  8. O’Donovan PJ, Livingston DM. BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis. 2010;31(6):961–7.

    PubMed  Google Scholar 

  9. Chinnadurai G. The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res. 2009;69(3):731–4.

    PubMed  CAS  Google Scholar 

  10. Zhang Q, Piston DW, Goodman RH. Regulation of corepressor function by nuclear NADH. Science. 2002;295(5561):1895–7.

    PubMed  CAS  Google Scholar 

  11. Fjeld CC, Birdsong WT, Goodman RH. Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor. Proc Natl Acad Sci USA. 2003;100(16):9202–7.

    PubMed  CAS  Google Scholar 

  12. Kolas NK et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science. 2007;318(5856):1637–40.

    PubMed  CAS  Google Scholar 

  13. Huen MSY et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell. 2007;131(5):901–14.

    PubMed  CAS  Google Scholar 

  14. Doil C et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009;136(3):435–46.

    PubMed  CAS  Google Scholar 

  15. Morris JR et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature. 2009;462(7275):886–90.

    PubMed  CAS  Google Scholar 

  16. Galanty Y et al. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature. 2009;462(7275):935–9.

    PubMed  CAS  Google Scholar 

  17. Yang H et al. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction. Nature. 2005;433(7026):653–7.

    PubMed  CAS  Google Scholar 

  18. San Filippo J et al. Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide. J Biol Chem. 2006;281(17):11649–57.

    PubMed  CAS  Google Scholar 

  19. Jensen RB et al. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature. 2010;467(7316):678–83.

    PubMed  CAS  Google Scholar 

  20. Thorslund T et al. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat Struct Mol Biol. 2010;17(10):1263–5.

    PubMed  CAS  Google Scholar 

  21. Liu J, Doty T, Gibson B, Heyer W. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat Struct Mol Biol. 2010;17(10):1260–2.

    PubMed  CAS  Google Scholar 

  22. Metcalfe KA et al. Screening for founder mutations in BRCA1 and BRCA2 in unselected Jewish women. J Clin Oncol. 2010;28(3):387–91.

    PubMed  CAS  Google Scholar 

  23. Antoniou A et al. 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. 2003;72(5):1117–30.

    PubMed  CAS  Google Scholar 

  24. Simchoni S et al. Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci USA. 2006;103(10):3770–4.

    PubMed  CAS  Google Scholar 

  25. Begg CB et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA: The Journal of the American Medical Association. 299(2):194–201.

  26. Antoniou AC et al. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet. 2010;42(10):885–92.

    PubMed  CAS  Google Scholar 

  27. Walker LC et al. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res. 2010;12(6):R102.

    PubMed  CAS  Google Scholar 

  28. Engel C et al. Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomark Prev. 2010;19(11):2859–68.

    CAS  Google Scholar 

  29. Antoniou AC et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008;82(4):937–48.

    PubMed  CAS  Google Scholar 

  30. Antoniou AC et al. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2009;18(22):4442–56.

    PubMed  CAS  Google Scholar 

  31. Antoniou AC et al. RAD51 135G–>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet. 2007;81(6):1186–200.

    PubMed  CAS  Google Scholar 

  32. Antoniou AC et al. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res. 2010;70(23):9742–54.

    PubMed  CAS  Google Scholar 

  33. Wang X et al. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2010;19(14):2886–97.

    PubMed  CAS  Google Scholar 

  34. Gaudet MM et al. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet. 2010;6(10):e1001183.

    PubMed  Google Scholar 

  35. Wacholder S et al. Performance of common genetic variants in breast-cancer risk models. N Engl J Med. 2010;362(11):986–93.

    PubMed  CAS  Google Scholar 

  36. Mitchell G et al. Mammographic density and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Res. 2006;66(3):1866–72.

    PubMed  CAS  Google Scholar 

  37. Lindström S et al. Common variants in ZNF365 are associated with both mammographic density and breast cancer risk. Nat Genet. 2011;43(3):185–7.

    PubMed  Google Scholar 

  38. Turnbull C et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet. 2010;42(6):504–7.

    PubMed  CAS  Google Scholar 

  39. Foulkes WD. Traffic control for BRCA1. N Engl J Med. 2010;362(8):755–6.

    PubMed  CAS  Google Scholar 

  40. D’Andrea AD. Susceptibility pathways in Fanconi’s anemia and breast cancer. N Engl J Med. 2010;362(20):1909–19.

    PubMed  Google Scholar 

  41. Renwick A et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38(8):873–5.

    PubMed  CAS  Google Scholar 

  42. The 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. 2004;74(6):1175–82.

    Google Scholar 

  43. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007;102(1):119–22.

    PubMed  CAS  Google Scholar 

  44. Bogdanova N et al. Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer. 2005;116(2):263–6.

    PubMed  CAS  Google Scholar 

  45. Kilpivaara O et al. CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer. 2004;111(4):543–7.

    PubMed  CAS  Google Scholar 

  46. Shaag A et al. Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet. 2005;14(4):555–63.

    PubMed  CAS  Google Scholar 

  47. Bogdanova N et al. CHEK2 mutation and hereditary breast cancer. J Clin Oncol. 2007;25(19):e26.

    PubMed  Google Scholar 

  48. Heikkinen K et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis. 2006;27(8):1593–9.

    PubMed  CAS  Google Scholar 

  49. Bogdanova N et al. Nijmegen Breakage Syndrome mutations and risk of breast cancer. Int J Cancer. 2008;122(4):802–6.

    PubMed  CAS  Google Scholar 

  50. Steffen J et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer. 2006;119(2):472–5.

    PubMed  CAS  Google Scholar 

  51. Seal S et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38(11):1239–41.

    PubMed  CAS  Google Scholar 

  52. Rahman N et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165–7.

    PubMed  CAS  Google Scholar 

  53. Erkko H et al. Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin Cancer Res. 2008;14(14):4667–71.

    PubMed  CAS  Google Scholar 

  54. Southey MC et al. A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res. 2010;12(6):R109.

    PubMed  CAS  Google Scholar 

  55. Swift M et al. Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res. 1976;36(1):209–15.

    PubMed  CAS  Google Scholar 

  56. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009;85(4):427–46.

    PubMed  CAS  Google Scholar 

  57. Bell DW et al. Heterozygous germ line hCHK2 Mutations in Li-Fraumeni syndrome. Science. 1999;286(5449):2528–31.

    PubMed  CAS  Google Scholar 

  58. Meijers-Heijboer H et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31(1):55–9.

    PubMed  CAS  Google Scholar 

  59. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75(6):1131–5.

    PubMed  CAS  Google Scholar 

  60. Cybulski C et al. A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. J Med Genet. 2006;43(11):863–6.

    PubMed  CAS  Google Scholar 

  61. Weischer M et al. Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol. 2007;25(1):57–63.

    PubMed  CAS  Google Scholar 

  62. Stolz A et al. The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat Cell Biol. 2010;12(5):492–9.

    PubMed  CAS  Google Scholar 

  63. Falck J et al. Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene. 2001;20(39):5503–10.

    PubMed  CAS  Google Scholar 

  64. Falck J et al. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature. 2001;410(6830):842–7.

    PubMed  CAS  Google Scholar 

  65. Weischer M et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol. 2008;26(4):542–8.

    PubMed  Google Scholar 

  66. Johnson N et al. Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study. Lancet. 2005;366(9496):1554–7.

    PubMed  CAS  Google Scholar 

  67. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry (CFR) case-control mutation screening study. Breast Cancer Res. 2011;13(1):R6.

    PubMed  Google Scholar 

  68. Lavin MF. ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene. 2007;26(56):7749–58.

    PubMed  CAS  Google Scholar 

  69. Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008;9(10):759–69.

    PubMed  CAS  Google Scholar 

  70. Waltes R et al. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet. 2009;84(5):605–16.

    PubMed  CAS  Google Scholar 

  71. Bartkova J et al. Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol. 2008;2(4):296–316.

    PubMed  Google Scholar 

  72. Akbari MR et al. Germline RAP80 mutations and susceptibility to breast cancer. Breast Cancer Res Treat. 2009;113(2):377–81.

    PubMed  CAS  Google Scholar 

  73. Novak DJ, Sabbaghian N, Maillet P, Chappuis PO, Foulkes WD, Tischkowitz M. Analysis of the genes coding for the BRCA1-interacting proteins, RAP80 and Abraxas (CCDC98), in high-risk, non-BRCA1/2, multiethnic breast cancer cases. Breast Cancer Res Treat. 2009;117(2):453–9.

    PubMed  Google Scholar 

  74. Osorio A et al. Evaluation of the BRCA1 interacting genes RAP80 and CCDC98 in familial breast cancer susceptibility. Breast Cancer Res Treat. 2009;113(2):371–6.

    PubMed  CAS  Google Scholar 

  75. Nikkilä J et al. Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function. Oncogene. 2009;28(16):1843–52.

    PubMed  Google Scholar 

  76. Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–9.

    PubMed  CAS  Google Scholar 

  77. Howlett NG et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297(5581):606–9.

    PubMed  CAS  Google Scholar 

  78. Levran O et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet. 2005;37(9):931–3.

    PubMed  CAS  Google Scholar 

  79. Levitus M et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005;37(9):934–5.

    PubMed  CAS  Google Scholar 

  80. Cantor SB et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001;105(1):149–60.

    PubMed  CAS  Google Scholar 

  81. Cantor S et al. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci USA. 2004;101(8):2357–62.

    PubMed  CAS  Google Scholar 

  82. Reid S et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39(2):162–4.

    PubMed  CAS  Google Scholar 

  83. Xia B et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet. 2007;39(2):159–61.

    PubMed  CAS  Google Scholar 

  84. Erkko H et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007;446(7133):316–9.

    PubMed  CAS  Google Scholar 

  85. Zhang F et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19(6):524–9.

    PubMed  CAS  Google Scholar 

  86. Zhang F et al. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res. 2009;7(7):1110–8.

    PubMed  CAS  Google Scholar 

  87. Xia B et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719–29.

    PubMed  CAS  Google Scholar 

  88. Dray E et al. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat Struct Mol Biol. 2010;17(10):1255–9.

    PubMed  CAS  Google Scholar 

  89. Tischkowitz M et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA. 2007;104(16):6788–93.

    PubMed  CAS  Google Scholar 

  90. Jones S et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217.

    PubMed  CAS  Google Scholar 

  91. Tischkowitz MD et al. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology. 2009;137(3):1183–6.

    PubMed  Google Scholar 

  92. Vaz F et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42(5):406–9.

    PubMed  CAS  Google Scholar 

  93. Meindl A et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42(5):410–4.

    PubMed  CAS  Google Scholar 

  94. Akbari MR et al. RAD51C germline mutations in breast and ovarian cancer patients. Breast Cancer Res. 2010;12(4):404.

    PubMed  Google Scholar 

  95. Zheng Y et al. Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat. 2010;124(3):857–61.

    PubMed  CAS  Google Scholar 

  96. Stoepker C et al. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet. 2011;43(2):138–41.

    PubMed  CAS  Google Scholar 

  97. Kim Y, Smogorzewska A, et al. Mutations of the SLX4 gene in Fanconi anemia. Nat Genet. 2011;43(2):142–6.

    PubMed  CAS  Google Scholar 

  98. Crossan GP et al. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nat Genet. 2011;43(2):147–52.

    PubMed  CAS  Google Scholar 

  99. Offit K, Garber JE. Time to check CHEK2 in families with breast cancer? J Clin Oncol. 2008;26(4):519–20.

    PubMed  Google Scholar 

  100. Antoniou AC et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer. 2002;86(1):76–83.

    PubMed  CAS  Google Scholar 

  101. Byrnes GB, Southey MC, Hopper JL. Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res. 2008;10(3):208.

    PubMed  Google Scholar 

  102. Cox A et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007;39(3):352–8.

    PubMed  CAS  Google Scholar 

  103. Easton DF et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087–93.

    PubMed  CAS  Google Scholar 

  104. Thomas G et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet. 2009;41(5):579–84.

    PubMed  CAS  Google Scholar 

  105. Zheng W et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet. 2009;41(3):324–8.

    PubMed  CAS  Google Scholar 

  106. Hunter DJ et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39(7):870–4.

    PubMed  CAS  Google Scholar 

  107. Milne RL et al. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042. J Natl Cancer Inst. 2009;101(14):1012–8.

    PubMed  CAS  Google Scholar 

  108. Stacey SN et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet. 2007;39(7):865–9.

    PubMed  CAS  Google Scholar 

  109. Stacey SN et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet. 2008;40(6):703–6.

    PubMed  CAS  Google Scholar 

  110. Ahmed S et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet. 2009;41(5):585–90.

    PubMed  CAS  Google Scholar 

  111. Moffa AB, Ethier SP. Differential signal transduction of alternatively spliced FGFR2 variants expressed in human mammary epithelial cells. J Cell Physiol. 2007;210(3):720–31.

    PubMed  CAS  Google Scholar 

  112. Jia L et al. Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet. 2009;5(8):e1000597.

    PubMed  Google Scholar 

  113. Ahmadiyeh N et al. 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci USA. 2010;107(21):9742–6.

    PubMed  CAS  Google Scholar 

  114. Kraft P, Hunter DJ. Genetic risk prediction—are we there yet? N Engl J Med. 2009;360(17):1701–3.

    PubMed  CAS  Google Scholar 

  115. Byrski T et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28(3):375–9.

    PubMed  CAS  Google Scholar 

  116. Bryant HE et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.

    PubMed  CAS  Google Scholar 

  117. Farmer H et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.

    PubMed  CAS  Google Scholar 

  118. Fong PC et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.

    PubMed  CAS  Google Scholar 

  119. Tutt A et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44.

    PubMed  CAS  Google Scholar 

  120. Audeh MW et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.

    PubMed  CAS  Google Scholar 

  121. Buisson R et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol. 2010;17(10):1247–54.

    PubMed  CAS  Google Scholar 

  122. Lakhani SR et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res. 2005;11(14):5175–80.

    PubMed  CAS  Google Scholar 

  123. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363(20):1938–48.

    PubMed  CAS  Google Scholar 

  124. Galizia E et al. BRCA1 expression in triple negative sporadic breast cancers. Anal Quant Cytol Histol. 2010;32(1):24–9.

    PubMed  Google Scholar 

  125. Turner NC et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26(14):2126–32.

    PubMed  CAS  Google Scholar 

  126. Baldassarre G et al. Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Mol Cell Biol. 2003;23(7):2225–38.

    PubMed  Google Scholar 

  127. Silver DP et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145–53.

    PubMed  CAS  Google Scholar 

  128. O’Shaughnessy J et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205–14.

    PubMed  Google Scholar 

  129. Sanofi aventis. Sanofi-aventis—R&D Keys figures 2011; http://en.sanofi-aventis.com/research_innovation/rd_key_figures/rd_key_figures.asp

Download references

Acknowledgments

We thank Marc Tischkowitz MB.BCh. Ph.D for helpful comments.

Work carried out in Dr. Foulkes’ laboratory is supported by Susan G. Komen for the Cure.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, H3G 1A4, Canada

    Andrew Y. Shuen & William D. Foulkes

  2. Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, 546 Pine Avenue West, Montreal, Quebec, H2W 1S6, Canada

    William D. Foulkes

  3. Department of Medical Genetics and Lady Davis Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada

    William D. Foulkes

Authors
  1. Andrew Y. Shuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William D. Foulkes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William D. Foulkes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shuen, A.Y., Foulkes, W.D. Inherited Mutations in Breast Cancer Genes—Risk and Response. J Mammary Gland Biol Neoplasia 16, 3–15 (2011). https://doi.org/10.1007/s10911-011-9213-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-011-9213-5

Keywords

Search

Navigation