Phenotype-Genotype Correlation in Familial Breast Cancer

  • Ana Cristina Vargas
  • Jorge S. Reis-Filho
  • Sunil R. Lakhani


Familial breast cancer accounts for a small but significant proportion of breast cancer cases worldwide. Identification of the candidate genes is always challenging specifically in patients with little or no family history. Therefore, a multidisciplinary team is required for the proper detection and further management of these patients. Pathologists have played a pivotal role in the cataloguing of genotypic-phenotypic correlations in families with hereditary cancer syndromes. These efforts have led to the identification of histological and phenotypic characteristics that can help predict the presence or absence of germline mutations of specific cancer predisposition genes. However, the panoply of cancer phenotypes associated with mutations of genes other than in BRCA1 is yet to be fully characterised; in fact, many cancer syndromes, germline mutations and gene sequence variants are under investigation for their possible morphological associations. Here we review the current understanding of phenotype-genotype correlation in familial breast cancer.


Familial breast cancer Germline mutation Phenotype Pathology 



ACV is a clinical fellow funded by the Ludwig Institute for Cancer Research (LICR). JSR-F is funded in part by Breakthrough Breast Cancer Research Centre. JSR-F is the recipient of the 2010 CRUK Future Leaders Prize.


  1. 1.
    Bray F, McCarron P, Parkin DM. The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res. 2004;6(6):229–39.PubMedGoogle Scholar
  2. 2.
    Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996;77(11):2318–24.PubMedGoogle Scholar
  3. 3.
    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. 2000;83(10):1301–8.Google Scholar
  4. 4.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.PubMedGoogle Scholar
  5. 5.
    Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265(5181):2088–90.PubMedGoogle Scholar
  6. 6.
    Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789–92.PubMedGoogle Scholar
  7. 7.
    Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–82.PubMedGoogle Scholar
  8. 8.
    Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, 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.PubMedGoogle Scholar
  9. 9.
    Lakhani SR, Gusterson BA, Jacquemier J, Sloane JP, Anderson TJ, van de Vijver MJ, et al. The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res. 2000;6(3):782–9.PubMedGoogle Scholar
  10. 10.
    Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst. 1998;90(15):1138–45.PubMedGoogle Scholar
  11. 11.
    Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, et al. Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 2010.Google Scholar
  12. 12.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.PubMedGoogle Scholar
  13. 13.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869–74.PubMedGoogle Scholar
  14. 14.
    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367–74.PubMedGoogle Scholar
  15. 15.
    Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, 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.PubMedGoogle Scholar
  16. 16.
    Foulkes WD, Brunet JS, Stefansson IM, Straume O, Chappuis PO, Begin LR, et al. The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 2004;64(3):830–5.PubMedGoogle Scholar
  17. 17.
    Armes JE, Venter DJ. The pathology of inherited breast cancer. Pathology. 2002;34(4):309–14.PubMedGoogle Scholar
  18. 18.
    Pinilla SM, Honrado E, Hardisson D, Benitez J, Palacios J. Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat. 2006;99(1):85–90.PubMedGoogle Scholar
  19. 19.
    Elsheikh SE, Green AR, Rakha EA, Samaka RM, Ammar AA, Powe D, et al. Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br J Cancer. 2008;99(2):327–34.PubMedGoogle Scholar
  20. 20.
    Rakha EA, Elsheikh SE, Aleskandarany MA, Habashi HO, Green AR, Powe DG, et al. Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res. 2009;15(7):2302–10.PubMedGoogle Scholar
  21. 21.
    Freneaux P, Stoppa-Lyonnet D, Mouret E, Kambouchner M, Nicolas A, Zafrani B, et al. Low expression of bcl-2 in Brca1-associated breast cancers. Br J Cancer. 2000;83(10):1318–22.PubMedGoogle Scholar
  22. 22.
    Vaziri SA, Tubbs RR, Darlington G, Casey G. Absence of CCND1 gene amplification in breast tumours of BRCA1 mutation carriers. Mol Pathol. 2001;54(4):259–63.PubMedGoogle Scholar
  23. 23.
    Elsheikh S, Green AR, Aleskandarany MA, Grainge M, Paish CE, Lambros MB, et al. CCND1 amplification and cyclin D1 expression in breast cancer and their relation with proteomic subgroups and patient outcome. Breast Cancer Res Treat. 2008;109(2):325–35.PubMedGoogle Scholar
  24. 24.
    Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, et al. Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res. 2003;9(10 Pt 1):3606–14.PubMedGoogle Scholar
  25. 25.
    Cortesi L, Turchetti D, Bertoni C, Bellei R, Mangone L, Vinceti M, et al. Comparison between genotype and phenotype identifies a high-risk population carrying BRCA1 mutations. Genes Chromosom Cancer. 2000;27(2):130–5.PubMedGoogle Scholar
  26. 26.
    van der Groep P, Bouter A, van der Zanden R, Siccama I, Menko FH, Gille JJ, et al. Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data. J Clin Pathol. 2006;59(6):611–7.PubMedGoogle Scholar
  27. 27.
    Gadzicki D, Schubert A, Fischer C, Milde S, Lehmann U, Steinemann D, et al. Histopathological criteria and selection algorithms for BRCA1 genetic testing. Cancer Genet Cytogenet. 2009;189(2):105–11.PubMedGoogle Scholar
  28. 28.
    Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, et al. Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat. 2005;90(1):5–14.PubMedGoogle Scholar
  29. 29.
    Visscher DW, Sarkar FH, Shimoyama RK, Crissman JD. Correlation between p53 immunostaining patterns and gene sequence mutations in breast carcinoma. Diagn Mol Pathol. 1996;5(3):187–93.PubMedGoogle Scholar
  30. 30.
    Phillips KA, Nichol K, Ozcelik H, Knight J, Done SJ, Goodwin PJ, et al. Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations. J Natl Cancer Inst. 1999;91(5):469–73.PubMedGoogle Scholar
  31. 31.
    Crook T, Brooks LA, Crossland S, Osin P, Barker KT, Waller J, et al. p53 mutation with frequent novel condons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours. Oncogene. 1998;17(13):1681–9.PubMedGoogle Scholar
  32. 32.
    Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res. 2009;69(8):3625–33.PubMedGoogle Scholar
  33. 33.
    Manie E, Vincent-Salomon A, Lehmann-Che J, Pierron G, Turpin E, Warcoin M, et al. High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. Cancer Res. 2009;69(2):663–71.PubMedGoogle Scholar
  34. 34.
    Laakso M, Loman N, Borg A, Isola J. Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors. Mod Pathol. 2005;18(10):1321–8.PubMedGoogle Scholar
  35. 35.
    Mulligan AM, Pinnaduwage D, Bane AL, Bull SB, O'Malley FP, Andrulis IL. CK8/18 expression, the basal phenotype, and family history in identifying BRCA1-associated breast cancer in the Ontario site of the Breast Cancer Family Registry. Cancer 2010.Google Scholar
  36. 36.
    Bane AL, Pinnaduwage D, Colby S, Bull SB, O'Malley FP, Andrulis IL. Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors. Breast Cancer Res Treat. 2009;117(1):183–91.PubMedGoogle Scholar
  37. 37.
    Domagala P, Huzarski T, Lubinski J, Gugala K, Domagala W. Immunophenotypic predictive profiling of BRCA1-associated breast cancer. Virchows Arch 2010.Google Scholar
  38. 38.
    Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15(8):907–13.PubMedGoogle Scholar
  39. 39.
    Lord CJ, Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol. 2008;8(4):363–9.PubMedGoogle Scholar
  40. 40.
    Tan DS, Marchio C, Reis-Filho JS. Hereditary breast cancer: from molecular pathology to tailored therapies. J Clin Pathol. 2008;61(10):1073–82.PubMedGoogle Scholar
  41. 41.
    Farshid G, Balleine RL, Cummings M, Waring P. Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing. Am J Surg Pathol. 2006;30(11):1357–66.PubMedGoogle Scholar
  42. 42.
    Lidereau R, Eisinger F, Champeme MH, Nogues C, Bieche I, Birnbaum D, et al. Major improvement in the efficacy of BRCA1 mutation screening using morphoclinical features of breast cancer. Cancer Res. 2000;60(5):1206–10.PubMedGoogle Scholar
  43. 43.
    Chang J, Hilsenbeck SG, Sng JH, Wong J, Ragu GC. Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients. Clin Cancer Res. 2001;7(6):1739–42.PubMedGoogle Scholar
  44. 44.
    Eisinger F, Nogues C, Guinebretiere JM, Peyrat JP, Bardou VJ, Noguchi T, et al. Novel indications for BRCA1 screening using individual clinical and morphological features. Int J Cancer. 1999;84(3):263–7.PubMedGoogle Scholar
  45. 45.
    Arnes JB, Brunet JS, Stefansson I, Begin LR, Wong N, Chappuis PO, et al. Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res. 2005;11(11):4003–11.PubMedGoogle Scholar
  46. 46.
    Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20(9):2310–8.PubMedGoogle Scholar
  47. 47.
    Rijnsburger AJ, Obdeijn IM, Kaas R, Tilanus-Linthorst MM, Boetes C, Loo CE, et al. BRCA1-Associated Breast Cancers Present Differently From BRCA2-Associated and Familial Cases: Long-Term Follow-Up of the Dutch MRISC Screening Study. J Clin Oncol 2010.Google Scholar
  48. 48.
    Collins LC, Martyniak A, Kandel MJ, Stadler ZK, Masciari S, Miron A, et al. Basal cytokeratin and epidermal growth factor receptor expression are not predictive of BRCA1 mutation status in women with triple-negative breast cancers. Am J Surg Pathol. 2009;33(7):1093–7.PubMedGoogle Scholar
  49. 49.
    Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO. Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol. 2008;39(6):857–65.PubMedGoogle Scholar
  50. 50.
    Beger C, Pierce LN, Kruger M, Marcusson EG, Robbins JM, Welcsh P, et al. Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc Natl Acad Sci USA. 2001;98(1):130–5.PubMedGoogle Scholar
  51. 51.
    Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26(14):2126–32.PubMedGoogle Scholar
  52. 52.
    Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011;41(2):210–20.PubMedGoogle Scholar
  53. 53.
    Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat. 2009;115(2):359–63.PubMedGoogle Scholar
  54. 54.
    Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, 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.PubMedGoogle Scholar
  55. 55.
    Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678–85.PubMedGoogle Scholar
  56. 56.
    Chappuis PO, Goffin J, Wong N, Perret C, Ghadirian P, Tonin PN, et al. A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet. 2002;39(8):608–10.PubMedGoogle Scholar
  57. 57.
    Simpson PT, Vargas AC, Al-Ejeh F, Khanna KK, Chenevix-Trench G, Lakhani SR. Application of molecular findings to the diagnosis and management of breast disease: recent advances and challenges. Hum Pathol 2010.Google Scholar
  58. 58.
    Balleine RL, Provan PJ, Pupo GM, Pathmanathan N, Cummings M, Farshid G, et al. Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families. Genes Chromosom Cancer. 2010;49(12):1082–94.PubMedGoogle Scholar
  59. 59.
    Honrado E, Osorio A, Milne RL, Paz MF, Melchor L, Cascon A, et al. Immunohistochemical classification of non-BRCA1/2 tumors identifies different groups that demonstrate the heterogeneity of BRCAX families. Mod Pathol. 2007;20(12):1298–306.PubMedGoogle Scholar
  60. 60.
    Da Silva L, Lakhani SR. Pathology of hereditary breast cancer. Mod Pathol. 2010;23 Suppl 2:S46–51.PubMedGoogle Scholar
  61. 61.
    Moffa AB, Tannheimer SL, Ethier SP. Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells. Mol Cancer Res. 2004;2(11):643–52.PubMedGoogle Scholar
  62. 62.
    Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, et al. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet. 2001;28(3):266–71.PubMedGoogle Scholar
  63. 63.
    Ongusaha PP, Ouchi T, Kim KT, Nytko E, Kwak JC, Duda RB, et al. BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest. Oncogene. 2003;22(24):3749–58.PubMedGoogle Scholar
  64. 64.
    Cheung AM, Elia A, Tsao MS, Done S, Wagner KU, Hennighausen L, et al. Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/−) mutant mice. Cancer Res. 2004;64(6):1959–65.PubMedGoogle Scholar
  65. 65.
    Bane AL, Beck JC, Bleiweiss I, Buys SS, Catalano E, Daly MB, et al. BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol. 2007;31(1):121–8.PubMedGoogle Scholar
  66. 66.
    Simpson PT, Reis-Filho JS, Lambros MB, Jones C, Steele D, Mackay A, et al. Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas. J Pathol. 2008;215(3):231–44.PubMedGoogle Scholar
  67. 67.
    Consortium BCL. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet. 1997;349(9064):1505–10.Google Scholar
  68. 68.
    Jacquemler J, Eisinger F, Guinebretiere JM, Stoppa-Lyonnet D, Sobol H. Intraductal component and BRCA1-associated breast cancer. Lancet. 1996;348(9034):1098.PubMedGoogle Scholar
  69. 69.
    Adem C, Reynolds C, Soderberg CL, Slezak JM, McDonnell SK, Sebo TJ, et al. Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer. 2003;97(1):1–11.PubMedGoogle Scholar
  70. 70.
    Claus EB, Petruzella S, Matloff E, Carter D. Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA. 2005;293(8):964–9.PubMedGoogle Scholar
  71. 71.
    Hwang ES, McLennan JL, Moore DH, Crawford BB, Esserman LJ, Ziegler JL. Ductal carcinoma in situ in BRCA mutation carriers. J Clin Oncol. 2007;25(6):642–7.PubMedGoogle Scholar
  72. 72.
    Gomez Garcia EB, Oosterwijk JC, Timmermans M, van Asperen CJ, Hogervorst FB, Hoogerbrugge N, et al. A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. Breast Cancer Res. 2009;11(1):R8.PubMedGoogle Scholar
  73. 73.
    Pensabene M, Spagnoletti I, Capuano I, Condello C, Pepe S, Contegiacomo A, et al. Two mutations of BRCA2 gene at exon and splicing site in a woman who underwent oncogenetic counseling. Ann Oncol. 2009;20(5):874–8.PubMedGoogle Scholar
  74. 74.
    Osorio A, Milne RL, Honrado E, Barroso A, Diez O, Salazar R, et al. Classification of missense variants of unknown significance in BRCA1 based on clinical and tumor information. Hum Mutat. 2007;28(5):477–85.PubMedGoogle Scholar
  75. 75.
    Tommasi S, Pilato B, Pinto R, Monaco A, Bruno M, Campana M, et al. Molecular and in silico analysis of BRCA1 and BRCA2 variants. Mutat Res. 2008;644(1–2):64–70.PubMedGoogle Scholar
  76. 76.
    Spearman AD, Sweet K, Zhou XP, McLennan J, Couch FJ, Toland AE. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol. 2008;26(33):5393–400.PubMedGoogle Scholar
  77. 77.
    Lovelock PK, Healey S, Au W, Sum EY, Tesoriero A, Wong EM, et al. Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants. J Med Genet. 2006;43(1):74–83.PubMedGoogle Scholar
  78. 78.
    Goldgar DE, Easton DF, Deffenbaugh AM, Monteiro AN, Tavtigian SV, Couch FJ. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet. 2004;75(4):535–44.PubMedGoogle Scholar
  79. 79.
    Chenevix-Trench G, Healey S, Lakhani S, Waring P, Cummings M, Brinkworth R, et al. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res. 2006;66(4):2019–27.PubMedGoogle Scholar
  80. 80.
    Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet. 2007;39(7):865–9.PubMedGoogle Scholar
  81. 81.
    Jia C, Cai Y, Ma Y, Fu D. Quantitative assessment of the effect of FGFR2 gene polymorphism on the risk of breast cancer. Breast Cancer Res Treat. 2010;124(2):521–8.PubMedGoogle Scholar
  82. 82.
    Dillon C, Spencer-Dene B, Dickson C. A crucial role for fibroblast growth factor signaling in embryonic mammary gland development. J Mammary Gland Biol Neoplasia. 2004;9(2):207–15.PubMedGoogle Scholar
  83. 83.
    Turner N, Lambros MB, Horlings HM, Pearson A, Sharpe R, Natrajan R, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;29(14):2013–23.PubMedGoogle Scholar
  84. 84.
    Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, 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.PubMedGoogle Scholar
  85. 85.
    Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J, Richesson DA, et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet. 2008;4(4):e1000054.PubMedGoogle Scholar
  86. 86.
    Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, Jonsson GF, et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet. 2008;40(6):703–6.PubMedGoogle Scholar
  87. 87.
    Yu K, Ganesan K, Miller LD, Tan P. A modular analysis of breast cancer reveals a novel low-grade molecular signature in estrogen receptor-positive tumors. Clin Cancer Res. 2006;12(11 Pt 1):3288–96.PubMedGoogle Scholar
  88. 88.
    Engel C, Versmold B, Wappenschmidt B, Simard J, Easton DF, Peock S, 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.Google Scholar
  89. 89.
    Antoniou AC, Sinilnikova OM, Simard J, Leone M, Dumont M, Neuhausen SL, et al. RAD51 135 G– > 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.PubMedGoogle Scholar
  90. 90.
    Gaudet MM, Kirchhoff T, Green T, Vijai J, Korn JM, Guiducci C, et al. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet. 2010;6(10):e1001183.PubMedGoogle Scholar
  91. 91.
    Hollestelle A, Pelletier C, Hooning M, Crepin E, Schutte M, Look M, et al. Prevalence of the variant allele rs61764370 T > G in the 3'UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families. Breast Cancer Res Treat 2010.Google Scholar
  92. 92.
    Lynch HT, Smyrk T, Lynch J. An update of HNPCC (Lynch syndrome). Cancer Genet Cytogenet. 1997;93(1):84–99.PubMedGoogle Scholar
  93. 93.
    Woods MO, Williams P, Careen A, Edwards L, Bartlett S, McLaughlin JR, et al. A new variant database for mismatch repair genes associated with Lynch syndrome. Hum Mutat. 2007;28(7):669–73.PubMedGoogle Scholar
  94. 94.
    Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261–8.PubMedGoogle Scholar
  95. 95.
    Chiaravalli AM, Furlan D, Facco C, Tibiletti MG, Dionigi A, Casati B, et al. Immunohistochemical pattern of hMSH2/hMLH1 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences. Virchows Arch. 2001;438(1):39–48.PubMedGoogle Scholar
  96. 96.
    Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260(5109):812–6.PubMedGoogle Scholar
  97. 97.
    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58(22):5248–57.PubMedGoogle Scholar
  98. 98.
    Kim H, Piao Z, Kim JW, Choi JS, Kim NK, Lee JM, et al. Expression of hMSH2 and hMLH1 in colorectal carcinomas with microsatellite instability. Pathol Res Pract. 1998;194(1):3–9.PubMedGoogle Scholar
  99. 99.
    Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 1997;57(21):4749–56.PubMedGoogle Scholar
  100. 100.
    Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002;123(6):1804–11.PubMedGoogle Scholar
  101. 101.
    Muller A, Edmonston TB, Corao DA, Rose DG, Palazzo JP, Becker H, et al. Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res. 2002;62(4):1014–9.PubMedGoogle Scholar
  102. 102.
    Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, et al. Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet. 2001;68(1):118–27.PubMedGoogle Scholar
  103. 103.
    Oliveira Ferreira F, Napoli Ferreira CC, Rossi BM, Toshihiko Nakagawa W, Aguilar Jr S, Monteiro Santos EM, et al. Frequency of extra-colonic tumors in hereditary nonpolyposis colorectal cancer (HNPCC) and familial colorectal cancer (FCC) Brazilian families: an analysis by a Brazilian Hereditary Colorectal Cancer Institutional Registry. Fam Cancer. 2004;3(1):41–7.PubMedGoogle Scholar
  104. 104.
    Shanley S, Fung C, Milliken J, Leary J, Barnetson R, Schnitzler M, et al. Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer. 2009;8(3):251–5.PubMedGoogle Scholar
  105. 105.
    Westenend PJ, Schutte R, Hoogmans MM, Wagner A, Dinjens WN. Breast cancer in an MSH2 gene mutation carrier. Hum Pathol. 2005;36(12):1322–6.PubMedGoogle Scholar
  106. 106.
    Barrow E, Robinson L, Alduaij W, Shenton A, Clancy T, Lalloo F, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet. 2009;75(2):141–9.PubMedGoogle Scholar
  107. 107.
    Wasielewski M, Riaz M, Vermeulen J, van den Ouweland A, Labrijn-Marks I, Olmer R, et al. Association of rare MSH6 variants with familial breast cancer. Breast Cancer Res Treat. 2010;123(2):315–20.PubMedGoogle Scholar
  108. 108.
    Jensen UB, Sunde L, Timshel S, Halvarsson B, Nissen A, Bernstein I, et al. Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat. 2009;120(3):777–82.PubMedGoogle Scholar
  109. 109.
    Walsh MD, Buchanan DD, Cummings MC, Pearson SA, Arnold ST, Clendenning M, et al. Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res. 2010;16(7):2214–24.PubMedGoogle Scholar
  110. 110.
    Schmitt FC, Soares R, Gobbi H, Milanezzi F, Santos-Silva F, Cirnes L, et al. Microsatellite instability in medullary breast carcinomas. Int J Cancer. 1999;82(5):644–7.PubMedGoogle Scholar
  111. 111.
    Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001;91(12):2417–22.PubMedGoogle Scholar
  112. 112.
    Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27(5):563–70.PubMedGoogle Scholar
  113. 113.
    Lacroix-Triki M, Lambros MB, Geyer FC, Suarez PH, Reis-Filho JS, Weigelt B. Absence of microsatellite instability in mucinous carcinomas of the breast. Int J Clin Exp Pathol. 2010;4(1):22–31.PubMedGoogle Scholar
  114. 114.
    Kim H, Jung JK, Park JH, Park C. Immunohistochemical characteristics of colorectal carcinoma with DNA replication errors. J Korean Med Sci. 1996;11(2):137–43.PubMedGoogle Scholar
  115. 115.
    Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002;20(4):1043–8.PubMedGoogle Scholar
  116. 116.
    Vasen HF, Morreau H, Nortier JW. Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer? Am J Hum Genet. 2001;68(6):1533–5.PubMedGoogle Scholar
  117. 117.
    de Leeuw WJ, van Puijenbroek M, Tollenaar RA, Cornelisse CJ, Vasen HF, Morreau H. Correspondence re: A. Muller et al., Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res., 62: 1014–1019, 2002. Cancer Res 2003;63(5):1148–9Google Scholar
  118. 118.
    Adem C, Soderberg CL, Cunningham JM, Reynolds C, Sebo TJ, Thibodeau SN, et al. Microsatellite instability in hereditary and sporadic breast cancers. Int J Cancer. 2003;107(4):580–2.PubMedGoogle Scholar
  119. 119.
    Khilko N, Bourne P, Qi Y, Ping T. Mismatch repair genes hMLH1 and hMSH2 may not play an essential role in breast carcinogenesis. Int J Surg Pathol. 2007;15(3):233–41.PubMedGoogle Scholar
  120. 120.
    Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121(6):1348–53.PubMedGoogle Scholar
  121. 121.
    Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg. 2000;87(8):992–1005.PubMedGoogle Scholar
  122. 122.
    Suriano G, Yew S, Ferreira P, Senz J, Kaurah P, Ford JM, et al. Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. Clin Cancer Res. 2005;11(15):5401–9.PubMedGoogle Scholar
  123. 123.
    Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet 2010.Google Scholar
  124. 124.
    Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297(21):2360–72.PubMedGoogle Scholar
  125. 125.
    Keller G, Vogelsang H, Becker I, Hutter J, Ott K, Candidus S, et al. Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am J Pathol. 1999;155(2):337–42.PubMedGoogle Scholar
  126. 126.
    Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004;41(7):508–17.PubMedGoogle Scholar
  127. 127.
    Masciari S, Larsson N, Senz J, Boyd N, Kaurah P, Kandel MJ, et al. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet. 2007;44(11):726–31.PubMedGoogle Scholar
  128. 128.
    Lei H, Sjoberg-Margolin S, Salahshor S, Werelius B, Jandakova E, Hemminki K, et al. CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk. Int J Cancer. 2002;98(2):199–204.PubMedGoogle Scholar
  129. 129.
    Hemminki K, Granstrom C. Morphological types of breast cancer in family members and multiple primary tumours: is morphology genetically determined? Breast Cancer Res. 2002;4(4):R7.PubMedGoogle Scholar
  130. 130.
    Zhu ZG, Yu YY, Zhang Y, Ji J, Zhang J, Liu BY, et al. Germline mutational analysis of CDH1 and pathologic features in familial cancer syndrome with diffuse gastric cancer/breast cancer proband in a Chinese family. Eur J Surg Oncol. 2004;30(5):531–5.PubMedGoogle Scholar
  131. 131.
    Da Silva L, Parry S, Reid L, Keith P, Waddell N, Kossai M, et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol. 2008;32(5):773–83.PubMedGoogle Scholar
  132. 132.
    Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003;22(3):183–98.PubMedGoogle Scholar
  133. 133.
    Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7(3):507–15.PubMedGoogle Scholar
  134. 134.
    Petrocelli T, Slingerland JM. PTEN deficiency: a role in mammary carcinogenesis. Breast Cancer Res. 2001;3(6):356–60.PubMedGoogle Scholar
  135. 135.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–7.PubMedGoogle Scholar
  136. 136.
    Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16(1):64–7.PubMedGoogle Scholar
  137. 137.
    Bau MG, Arisio R, Cristini G, Bertone E, Campogrande M. Screening-detected breast carcinoma in a patient with Cowden syndrome. Breast. 2004;13(3):239–41.PubMedGoogle Scholar
  138. 138.
    Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001;14(7):672–6.PubMedGoogle Scholar
  139. 139.
    Uppal S, Mistry D, Coatesworth AP. Cowden disease: a review. Int J Clin Pract. 2007;61(4):645–52.PubMedGoogle Scholar
  140. 140.
    Tsao H. Update on familial cancer syndromes and the skin. J Am Acad Dermatol. 2000;42(6):939–69. quiz 970–2.PubMedGoogle Scholar
  141. 141.
    Fackenthal JD, Marsh DJ, Richardson AL, Cummings SA, Eng C, Robinson BG, et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001;38(3):159–64.PubMedGoogle Scholar
  142. 142.
    Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351(5):427–37.PubMedGoogle Scholar
  143. 143.
    Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M. Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Hum Pathol. 1998;29(1):47–53.PubMedGoogle Scholar
  144. 144.
    Lachlan KL, Lucassen AM, Bunyan D, Temple IK. Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet. 2007;44(9):579–85.PubMedGoogle Scholar
  145. 145.
    Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI, Boyd J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res. 1997;57(17):3657–9.PubMedGoogle Scholar
  146. 146.
    Braud AC, de Rocquancourt A, Marty M, Espie M. Cowden disease and Lhermitte Duclos disease, markers of breast carcinoma: report of two patients. Ann Oncol. 1999;10(10):1241–3.PubMedGoogle Scholar
  147. 147.
    Reifenberger J, Rauch L, Beckmann MW, Megahed M, Ruzicka T, Reifenberger G. Cowden's disease: clinical and molecular genetic findings in a patient with a novel PTEN germline mutation. Br J Dermatol. 2003;148(5):1040–6.PubMedGoogle Scholar
  148. 148.
    Sabate JM, Gomez A, Torrubia S, Blancas C, Sanchez G, Alonso MC, et al. Evaluation of breast involvement in relation to Cowden syndrome: a radiological and clinicopathological study of patients with PTEN germ-line mutations. Eur Radiol. 2006;16(3):702–6.PubMedGoogle Scholar
  149. 149.
    Singh B, Ittmann MM, Krolewski JJ. Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus. Genes Chromosom Cancer. 1998;21(2):166–71.PubMedGoogle Scholar
  150. 150.
    Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R. Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene. 1998;17(1):123–7.PubMedGoogle Scholar
  151. 151.
    Dedes KJ, Wetterskog D, Mendes-Pereira AM, Natrajan R, Lambros MB, Geyer FC, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75.PubMedGoogle Scholar
  152. 152.
    Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6–7):315–22.PubMedGoogle Scholar
  153. 153.
    Li FP, Fraumeni Jr JF. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71(4):747–52.PubMedGoogle Scholar
  154. 154.
    Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233–8.PubMedGoogle Scholar
  155. 155.
    Li FP, Fraumeni Jr JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48(18):5358–62.PubMedGoogle Scholar
  156. 156.
    Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009;27(26):e108–9. author reply e110.PubMedGoogle Scholar
  157. 157.
    Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003;21(3):313–20.PubMedGoogle Scholar
  158. 158.
    Yamada H, Shinmura K, Yamamura Y, Kurachi K, Nakamura T, Tsuneyoshi T, et al. Identification and characterization of a novel germline p53 mutation in a patient with glioblastoma and colon cancer. Int J Cancer. 2009;125(4):973–6.PubMedGoogle Scholar
  159. 159.
    Ruijs MW, Verhoef S, Rookus MA, Pruntel R, van der Hout AH, Hogervorst FB, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet. 2010;47(6):421–8.PubMedGoogle Scholar
  160. 160.
    Blanco A, Grana B, Fachal L, Santamarina M, Cameselle-Teijeiro J, Ruiz-Ponte C, et al. Beyond BRCA1 and BRCA2 wild-type breast and/or ovarian cancer families: germline mutations in TP53 and PTEN. Clin Genet. 2010;77(2):193–6.PubMedGoogle Scholar
  161. 161.
    Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27(8):1250–6.PubMedGoogle Scholar
  162. 162.
    Wilson JR, Bateman AC, Hanson H, An Q, Evans G, Rahman N, et al. A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet. 2010;47(11):771–4.PubMedGoogle Scholar
  163. 163.
    Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001;20(34):4621–8.PubMedGoogle Scholar
  164. 164.
    Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268(5218):1749–53.PubMedGoogle Scholar
  165. 165.
    Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF, Weber B, et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res. 2000;60(12):3299–304.PubMedGoogle Scholar
  166. 166.
    Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3(3):155–68.PubMedGoogle Scholar
  167. 167.
    Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005;97(11):813–22.PubMedGoogle Scholar
  168. 168.
    Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38(8):873–5.PubMedGoogle Scholar
  169. 169.
    Paglia LL, Lauge A, Weber J, Champ J, Cavaciuti E, Russo A, et al. ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy. Breast Cancer Res Treat. 2010;119(2):443–52.PubMedGoogle Scholar
  170. 170.
    Fletcher O, Johnson N. dos Santos Silva I, Orr N, Ashworth A, Nevanlinna H, et al. Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls. Cancer Epidemiol Biomark Prev. 2010;19(9):2143–51.Google Scholar
  171. 171.
    Tavtigian SV, Oefner PJ, Babikyan D, Hartmann A, Healey S, Le Calvez-Kelm F, et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009;85(4):427–46.PubMedGoogle Scholar
  172. 172.
    Balleine RL, Murali R, Bilous AM, Farshid G, Waring P, Provan P, et al. Histopathological features of breast cancer in carriers of ATM gene variants. Histopathology. 2006;49(5):523–32.PubMedGoogle Scholar
  173. 173.
    Tommiska J, Bartkova J, Heinonen M, Hautala L, Kilpivaara O, Eerola H, et al. The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene. 2008;27(17):2501–6.PubMedGoogle Scholar
  174. 174.
    Barroso E, Pita G, Arias JI, Menendez P, Zamora P, Blanco M, et al. The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features. Breast Cancer Res Treat. 2009;118(3):655–60.PubMedGoogle Scholar
  175. 175.
    D'Andrea AD. Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med. 2010;362(20):1909–19.PubMedGoogle Scholar
  176. 176.
    Levy-Lahad E. Fanconi anemia and breast cancer susceptibility meet again. Nat Genet. 2010;42(5):368–9.PubMedGoogle Scholar
  177. 177.
    Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res. 2009;668(1–2):4–10.PubMedGoogle Scholar
  178. 178.
    Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet. 2008;40(1):17–22.PubMedGoogle Scholar
  179. 179.
    Berwick M, Satagopan JM, Ben-Porat L, Carlson A, Mah K, Henry R, et al. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 2007;67(19):9591–6.PubMedGoogle Scholar
  180. 180.
    Tischkowitz M, Xia B, Sabbaghian N, Reis-Filho JS, Hamel N, Li G, et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA. 2007;104(16):6788–93.PubMedGoogle Scholar
  181. 181.
    Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–9.PubMedGoogle Scholar
  182. 182.
    Mavaddat N, Dunning AM, Ponder BA, Easton DF, Pharoah PD. Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer. Cancer Epidemiol Biomark Prev. 2009;18(1):255–9.Google Scholar
  183. 183.
    San Filippo J, Sung P, Klein H. Mechanism of eukaryotic homologous recombination. Annu Rev Biochem. 2008;77:229–57.PubMedGoogle Scholar
  184. 184.
    Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42(5):406–9.PubMedGoogle Scholar
  185. 185.
    Zheng Y, Zhang J, Hope K, Niu Q, Huo D, Olopade OI. Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat. 2010;124(3):857–61.PubMedGoogle Scholar
  186. 186.
    Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997;88(2):265–75.PubMedGoogle Scholar
  187. 187.
    Barbano R, Copetti M, Perrone G, Pazienza V, Muscarella LA, Balsamo T, et al. High RAD51 mRNA expression characterize ER-positive/PR-negative breast cancers and is associated with patient's outcome. Int J Cancer 2010.Google Scholar
  188. 188.
    Chehab NH, Malikzay A, Appel M, Halazonetis TD. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev. 2000;14(3):278–88.PubMedGoogle Scholar
  189. 189.
    Lee JS, Collins KM, Brown AL, Lee CH, Chung JH. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature. 2000;404(6774):201–4.PubMedGoogle Scholar
  190. 190.
    Wu X, Webster SR, Chen J. Characterization of tumor-associated Chk2 mutations. J Biol Chem. 2001;276(4):2971–4.PubMedGoogle Scholar
  191. 191.
    Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002;71(2):432–8.PubMedGoogle Scholar
  192. 192.
    Iniesta MD, Gorin MA, Chien LC, Thomas SM, Milliron KJ, Douglas JA, et al. Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America. Cancer Genet Cytogenet. 2010;202(2):136–40.PubMedGoogle Scholar
  193. 193.
    Zhang S, Phelan CM, Zhang P, Rousseau F, Ghadirian P, Robidoux A, et al. Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study. Cancer Res. 2008;68(7):2154–7.PubMedGoogle Scholar
  194. 194.
    Schmidt MK, Tollenaar RA, de Kemp SR, Broeks A, Cornelisse CJ, Smit VT, et al. Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol. 2007;25(1):64–9.PubMedGoogle Scholar
  195. 195.
    de Bock GH, Schutte M, Krol-Warmerdam EM, Seynaeve C, Blom J, Brekelmans CT, et al. Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet. 2004;41(10):731–5.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ana Cristina Vargas
    • 1
  • Jorge S. Reis-Filho
    • 2
  • Sunil R. Lakhani
    • 1
    • 3
    • 4
    • 5
  1. 1.UQ Centre for Clinical ResearchThe University of QueenslandBrisbaneAustralia
  2. 2.The Breakthrough Breast Cancer Research CentreInstitute of Cancer ResearchLondonUK
  3. 3.School of MedicineThe University of QueenslandBrisbaneAustralia
  4. 4.Pathology QueenslandThe Royal Brisbane & Women’s HospitalBrisbaneAustralia
  5. 5.The University of Queensland Centre for Clinical ResearchRoyal Brisbane & Women’s HospitalHerstonAustralia

Personalised recommendations