Skip to main content
SpringerLink
Log in

Inherited Breast Cancer

  • Chapter
Molecular Pathology in Clinical Practice

  • 3573 Accesses

Abstract

Inherited mutations in high-risk breast cancer-predisposing genes explain approximately 10 % of all breast cancer cases. Most of these mutations are in the BRCA1 and BRCA2 genes, as part of hereditary breast and ovarian cancer (HBOC). Others are in genes associated with syndromes which include a wider spectrum of malignancies and/or distinct clinical features. Molecular analysis, guided by clinical criteria and application of risk assessment models, currently reveal the underlying cause in roughly half of hereditary breast cancer families. Women who have inherited mutations in the HBOC genes have a high lifetime risk for both breast cancer and ovarian cancer. In BRCA1 and BRCA2 carriers, effective surveillance and prevention measures (such as risk-reduction salpingo-oophorectomy) reduce morbidity and mortality, and mutation status can enable targeted therapy (such as PARP inhibitors).

Clinical genetic analysis for suspected inherited predisposition to breast cancer, previously mostly limited to Sanger sequencing of BRCA1 and BRCA2, has been transformed by next-generation sequencing (NGS) technology, which enables rapid and simultaneous analysis of multiple genes. The ability of NGS assays to accurately and cost-effectively detect all classes of mutations, including large rearrangements, offers an important advantage over previous testing strategies. However, clinical interpretation of variants remains a significant challenge even in the well-studied BRCA1 and BRCA2 genes, let alone other breast cancer-associated genes. Testing numerous individuals is revealing an ever greater number of rare variations, whose effect on gene and protein function remains unclear. Reporting such variants of unknown significance is not driven by their clinical utility, and there is an urgent need for improved strategies to assess their functional and clinical effects. Testing genes beyond BRCA1 and BRCA2 is further complicated by the current lack of evidence-based guidelines for surveillance and prevention measures, even for carriers of mutations in genes considered to be clear moderate-risk predisposition genes.

Nevertheless, identifying cancer-predisposing mutations is increasingly feasible, will lead to optimized, personalized care for mutation carriers, and is likely to provide insights of broader relevance to cancer.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Parkin DM, Boyd L, Walker LC. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Br J Cancer. 2011;105 Suppl 2:S77–81.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Hemminki K, Granstrom C, Czene K. Attributable risks for familial breast cancer by proband status and morphology: a nationwide epidemiologic study from Sweden. Int J Cancer. 2002;100:214–9.

    Article  CAS  PubMed  Google Scholar 

  3. Pharoah PD, Day NE, Duffy S, et al. Family history and the risk of breast cancer: a systematic review and metaanalysis. Int J Cancer. 1997;71:800–9.

    Article  CAS  PubMed  Google Scholar 

  4. Mavaddat N, Pharoah P, Blows F, et al. Familial relative risks for breast cancer by pathological subtype: a population-based cohort study. Breast Cancer Res. 2010;12(1):R10.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Bevier M, Sundquist K, Hemminki K. Risk of breast cancer in families of multiple affected women and men. Breast Cancer Res Treat. 2012;132(2):723–8.

    Article  PubMed  Google Scholar 

  6. 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;83:1301–8.

    Article  PubMed Central  Google Scholar 

  7. Offit K. Risk Counseling and Management Clinical Cancer Genetics. New York: Wiley-Liss; 1998.

    Google Scholar 

  8. Daly MB, Axilbund JE, Buys S, et al. Genetic/familial high-risk assessment: breast and ovarian. National Comprehensive Cancer Network. J Natl Compr Canc Netw. 2010;8(5):562–94.

    CAS  PubMed  Google Scholar 

  9. de Jong MM, Nolte IM, Meerman GJ, et al. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J Med Genet. 2002;39:225–42.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31:55–9.

    Article  CAS  PubMed  Google Scholar 

  11. McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010;141(2):210–7.

    Article  CAS  PubMed  Google Scholar 

  12. Meindl A, Hellebrand H, Wiek C, 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.

    Article  CAS  PubMed  Google Scholar 

  13. Loveday C, Turnbull C, Ramsay E, Breast Cancer Susceptibility Collaboration (UK), et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43(9):879–82.

    Article  CAS  PubMed  Google Scholar 

  14. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.

    Article  CAS  PubMed  Google Scholar 

  15. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–92.

    Article  CAS  PubMed  Google Scholar 

  16. Chen Y, Farmer AA, Chen CF, et al. BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res. 1996;56:3168–72.

    CAS  PubMed  Google Scholar 

  17. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011;12(1):68–78.

    Article  PubMed  CAS  Google Scholar 

  18. Fan S, Wang J, Yuan R, et al. BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science. 1999;284:1354–6.

    Article  CAS  PubMed  Google Scholar 

  19. Zhu Q, Pao GM, Huynh AM, et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature. 2011;477:179–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–82.

    Article  CAS  PubMed  Google Scholar 

  21. Ferla R, CaloV, Cascio S et al. (2007). Founder mutations in BRCA1 and BRCA2 genes. Ann. Oncol. 18 Suppl 6, vi93-vi98.

    Google Scholar 

  22. Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997;60:1013–20.

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Moller P, Heimdal K, Apold J, et al. Genetic epidemiology of BRCA1 mutations in Norway. Eur J Cancer. 2001;37:2428–34.

    Article  CAS  PubMed  Google Scholar 

  24. Einbeigi Z, Bergman A, Kindblom LG, et al. A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer. Eur J Cancer. 2001;37:1904–9.

    Article  CAS  PubMed  Google Scholar 

  25. Menkiszak J, Gronwald J, Gorski B, et al. Hereditary ovarian cancer in Poland. Int J Cancer. 2003;106:942–5.

    Article  CAS  PubMed  Google Scholar 

  26. Olopade OI, Fackenthal JD, Dunston G, et al. Breast cancer genetics in African Americans. Cancer. 2003;97(suppl):236–45.

    Article  CAS  PubMed  Google Scholar 

  27. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643–6.

    Article  CAS  PubMed  Google Scholar 

  28. Moslehi R, Chu W, Karlan B, et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet. 2000;66(4):1259–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480–90.

    Article  CAS  PubMed  Google Scholar 

  30. Thorlacius S, Sigurdsson S, Bjarnadottir H, et al. Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet. 1997;60:1079–84.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. The BRCA1 Exon 13 Duplication Screening Group. The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. Am J Hum Genet. 2000;67(1):207–12.

    Article  Google Scholar 

  32. Petrij-Bosch A, Peelen T, van Vliet M, et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet. 1997;17:341–5.

    Article  CAS  PubMed  Google Scholar 

  33. Ford D, Easton DF, Stratton M, 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Antoniou AC, Pharoah PD, Easton DF, et al. BRCA1 and BRCA2 cancer risks. J Clin Oncol. 2006;24(20):3312–4.

    Article  PubMed  Google Scholar 

  35. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336(20):1401–8.

    Article  CAS  PubMed  Google Scholar 

  36. Antoniou AC, Pharoah PD, Narod S, 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;72:1117–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1 mutation carriers. Lancet. 1994;343:692–5.

    Article  CAS  PubMed  Google Scholar 

  38. Lizarraga I, Sugg S, Weigel R, et al. Review of risk factors for the development of contralateral breast cancer. Am J Surgery. 2013;206:704–8.

    Article  Google Scholar 

  39. Metcalfe K, Gershman S, Lynch HT, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2011;104:1384–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA. 2006;296:185–92.

    Article  CAS  PubMed  Google Scholar 

  41. Risch HA, McLaughlin JR, Cole DC, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population of 649 women with ovarian cancer. Am J Hum Genet. 2001;68:700–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 2002;62:3789–93.

    CAS  PubMed  Google Scholar 

  43. Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013;62:339–47.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Slater EP, Langer P, Fendrich V, et al. Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families. Fam Cancer. 2010;9:335–43.

    Article  CAS  PubMed  Google Scholar 

  45. Thompson D, Easton DF. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94:1358–65.

    Article  CAS  PubMed  Google Scholar 

  46. Van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet. 2005;42:711–9.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Iqbal J, Ragone A, Lubinski J, et al. The incidence of pancreatic cancer in BRCA1and BRCA2 mutation carriers. Br J Cancer. 2012;107(12):2005–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Finch AP, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547–53.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Bayraktar S, Glück S. Systemic therapy options in BRCA mutation-associated breast cancer. Breast Cancer Res Treat. 2012;135(2):355–66.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.

    Article  CAS  PubMed  Google Scholar 

  53. American Association for Cancer Research (2015). Olaparib Approved for Advanced Ovarian Cancer. Cancer Discov. (ahead of print).

    Google Scholar 

  54. Bhalla A, Saif MW. PARP-inhibitors in BRCA-associated pancreatic cancer. JOP. 2014;15(4):340–3.

    PubMed  Google Scholar 

  55. Brough R, Frankum JR, Costa-Cabral S, et al. Searching for synthetic lethality in cancer. Curr Opin Genet Dev. 2011;21:34–41.

    Article  CAS  PubMed  Google Scholar 

  56. Carey LA, Perou CM, Livasy CA, et al. Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–502.

    Article  CAS  PubMed  Google Scholar 

  57. Turner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA1 phenotype. Oncogene. 2006;25:5846–53.

    Article  CAS  PubMed  Google Scholar 

  58. Bane AL, Beck JC, Bleiweiss I, 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;31:121–8.

    Article  PubMed  Google Scholar 

  59. Lakhani SR, Gusterson BA, Jacquemier J, 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;6:782–9.

    CAS  PubMed  Google Scholar 

  60. Perez-Valles A, Martorell-Cebolla M, Nogueira-Vazquez, et al. The usefulness of antibodies to the BRCA1 protein in detecting the mutated BRCA1 gene. An immunohistochemical study. J Clin Pathol. 2001;54(6):476–80.

    Google Scholar 

  61. Meisel JL, Hyman DM, Garg K, et al. The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer. Ann Oncol. 2014; 25(12):2372–8.

    Google Scholar 

  62. Vaz FH, Machado PM, Brandao RD, et al. Familial breast/ovarian cancer and BRCA1/2 genetic screening: The role of immunohistochemistry as an additional method in the selection of patients. J Histochem Cytochem. 2007;55:1105–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Watson P, Lieberman R, Snyder C, et al. Detecting BRCA2 protein truncation in tissue biopsies to identify breast cancers that arise in BRCA2 gene mutation carriers. J Clin Oncol. 2009;27(24):3894–900.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. 2014;111(39):14205–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998;62(1):145–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Biswas S, Tankhiwale N, Blackford A, et al. Assessing the added value of breast tumor markers in genetic risk prediction model BRCAPRO. Breast Cancer Res Treat. 2012;133(1):347–55.

    Article  CAS  PubMed  Google Scholar 

  67. van Harssel JJ, van Roozendaal CE, Detisch Y, et al. Efficiency of BRCAPRO and Myriad II mutation probability thresholds versus cancer history criteria alone for BRCA1/2 mutation detection. Fam Cancer. 2010;9(2):193–201.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Antoniou AC, Cunningham AP, Peto J, et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer. 2008;98:1457–66.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Antoniou AC, Hardy R, Walker L, et al. Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J Med Genet. 2008;45(7):425–31.

    Article  CAS  PubMed  Google Scholar 

  70. Schneegans SM, Rosenberger A, Engel U, et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2011;11(2):181–8.

    Article  PubMed Central  CAS  Google Scholar 

  71. Tyrer JP, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23(7):1111–30.

    Article  PubMed  Google Scholar 

  72. Evans GR, Lalloo F. Development of a scoring system to screen for BRCA1/2 mutations. Methods Mol Biol. 2010;653:237–47.

    Article  CAS  PubMed  Google Scholar 

  73. Kurian AW, Gong GD, John EM, et al. Performance of prediction models for BRCA mutation carriage in three racial/ethnic groups: findings from the Northern California Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev Biomarkers Prev. 2009;18(4):1084–91.

    Article  CAS  Google Scholar 

  74. Kurian AW, Gong GD, Chun NM, et al. Performance of BRCA1/2 mutation prediction models in Asian Americans. J Clin Oncol. 2008;26(29):4752–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Gerhardus A, Schleberger H, Schleberger B, et al. Diagnostic accuracy of methods for the detection of BRCA1 and BRCA2 mutations: a systematic review. Eur J Hum Genet. 2007;6:619–27.

    Article  CAS  Google Scholar 

  76. Spearman AD, Sweet K, Zhou XP, et al. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol. 2008;26(33):5393–400.

    Article  PubMed Central  PubMed  Google Scholar 

  77. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295(12):1379–88.

    Article  CAS  PubMed  Google Scholar 

  78. Palma MD, Domchek SM, Stopfer J, et al. The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 high risk breast cancer families. Cancer Res. 2008;68(17):7006–14.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  79. Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. Breast Cancer Res Treat. 2011;125(2):325–49.

    Article  CAS  PubMed  Google Scholar 

  80. Hendrickson B, Judkins T, Ward BD, et al. Prevalence results for five previously reported and recurrent BRCA1 genetic rearrangement mutations in 20,000 patients from hereditary breast/ovarian cancer families. Genes Chromosomes Cancer. 2005;43:309–13.

    Article  CAS  PubMed  Google Scholar 

  81. Judkins T, Rosenthal E, Arnell C, et al. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer. 2012;118(21):5210–6.

    Google Scholar 

  82. Schouten JP, McElgunn CJ, Waaijer R et al. (2002). Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nuc. Acid Res. 30(12):e57.

    Google Scholar 

  83. Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(28):12629–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Cheeseman K, Rouleau E, Vannier A, et al. A diagnostic genetic test for the physical mapping of germline rearrangements in the susceptibility breast cancer genes BRCA1 and BRCA2. Hum Mutat. 2012;33(6):998–1009.

    Article  CAS  PubMed  Google Scholar 

  85. Berglund EC, Kiialainen A, Syvänen AC, et al. Next-generation sequencing technologies and applications for human genetic history and forensics. Investigative Genet. 2011;2:23.

    Article  CAS  Google Scholar 

  86. Metzker ML. Sequencing technologies—the next generation. Nat Rev. 2010;11:31–46.

    Article  CAS  Google Scholar 

  87. Morgan JE, Carr IM, Sheridan E, et al. Genetic diagnosis of familial Breast Cancer using clonal sequencing. Hum Mutat. 2010;4:484–91.

    Article  CAS  Google Scholar 

  88. De Leeneer K, De Schrijver J, Clement L, et al. Practical tools to implement massive parallel pyrosequencing of PCR products in next generation molecular diagnostics. PLoS One. 2011;6(9), e25531.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  89. De Leeneer K, Hellemans J, De Schrijver J, et al. Massive parallel amplicon sequencing of the breast cancer genes BRCA1 and BRCA2: opportunities, challenges, and limitations. Hum Mutat. 2011;32(3):335–44.

    Article  PubMed  CAS  Google Scholar 

  90. Herman I, Borrás E, de Sousa DM, et al. Detection of genomic variations in BRCA1 and BRCA2 genes by long-range PCR and next-generation sequencing. J Mol Diagn. 2012;14(3):286–93.

    Google Scholar 

  91. Ozcelik H, Shi X, Chang MC, et al. Long-Range PCR and Next-Generation Sequencing of BRCA1 and BRCA2 in Breast Cancer. J Mol Diagn. 2012;14(5):467–75.

    Article  CAS  PubMed  Google Scholar 

  92. Korbel JO, Urban AE, Affourtit JP, et al. Paired-end mapping reveals extensive structural variation in the human genome. Science. 2007;318:420–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Campbell PJ, Stephens PJ, Pleasance ED, et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008;40:722–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505(7483):302–8.

    Article  CAS  PubMed  Google Scholar 

  95. Domchek SM, Nathanson KL. Panel testing for inherited susceptibility to breast, ovarian, and colorectal cancer. Genet Med. 2014;16(11):827–9.

    Article  CAS  PubMed  Google Scholar 

  96. Comino-Mendez I, Gracia-Aznárez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–7.

    Article  CAS  PubMed  Google Scholar 

  97. Smith MJ, O’Sullivan J, Bhaskar SS, et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat Genet. 2013;45(3):295–8.

    Article  CAS  PubMed  Google Scholar 

  98. Snape K, Ruark E, Tarpey P, et al. Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer. Breast Cancer Res Treat. 2012;134(1):429–33.

    Article  PubMed Central  PubMed  Google Scholar 

  99. Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Ann Rev Genomics Hum Genet. 2008;9:321–45.

    Article  CAS  Google Scholar 

  100. Berry DA, Iversen ES, Gudbjartsson DF, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002;20(11):2701–12.

    Article  CAS  PubMed  Google Scholar 

  101. Ghiorzo P. Genetic predisposition to pancreatic cancer. World J Gastroenterol. 2014;20(31):10778–89.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  102. Maxwell KN, Wubbenhorst B, D’Andrea K (2014). Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. doi: 10.1038/gim.2014.176. [Epub ahead of print]

    Google Scholar 

  103. Kurian AW, Hare EE, Mills MA. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014;32(19):2001–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Abecasis GR, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.

    Article  PubMed  CAS  Google Scholar 

  105. Murray ML, Cerrato F, Bennett RL, et al. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: Variant reclassification and surgical decisions. Genet Med. 2011;13(12):998–1005.

    Article  CAS  PubMed  Google Scholar 

  106. Ng PC, Henikoff S. Accounting for human polymorphisms predicted to affect protein function. Genome Res. 2002;12(3):436–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Ramensky V, Bork P, Sunyaev S, et al. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002;30(17):3894–900.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Abkevich V, Zharkikh A, Deffenbaugh A, et al. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 2004;41(7):492–507.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Tavtigian SV, Samollow PB, de Silva D, et al. An analysis of unclassified missense substitutions in human BRCA1. Fam Cancer. 2006;5(1):77–88.

    Article  CAS  PubMed  Google Scholar 

  110. Théry JC, Krieger S, Gaildrat P, et al. Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. Eur J Hum Genet. 2001;10:1052–8.

    Google Scholar 

  111. Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007;44:1–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Domchek SM, Tang J, Stopfer J, et al. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov. 2013;3(4):399–405.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Sawyer SL, Tian L, Kähkönen M, et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov. 2015;5(2):135–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Collins N, McManus R, Wooster R, et al. Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13. Oncogene. 1995;10(8):1673–5.

    CAS  PubMed  Google Scholar 

  115. Hofstra RM, Spurdle AB, Eccles D, Unclassified Genetic Variants Working Group IARC, et al. Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance. Hum Mutat. 2008;29:1292–303.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Farrugia DJ, Agarwal MK, Pankratz VS, et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res. 2008;68(9):3523–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Iversen ES, Couch FJ, Goldgar DE, et al. A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. Cancer Epidemiol Biomarkers Prev. 2011;20(6):1078–88.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Millot GA, Carvalho MA, Caputo SM, on behalf of the ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) Consortium Functional Assay Working Group, et al. A guide for functional analysis of BRCA1 variants of uncertain significance. Hum Mutat. 2012;33(11):1526–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Hendriks G, Morolli B, Calléja FM, et al. An efficient pipeline for the generation and functional analysis of human BRCA2 variants of uncertain significance. Hum Mutat. 2014;11:1382–91.

    Google Scholar 

  120. Spurdle AB, Healey S, Devereau A, et al. ENIGMA-evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in the BRCA1 and BRCA2 genes. Hum Mutat. 2012;33(1):2–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Mattocks CJ, Morris MA, Matthijs G, Group EGV, et al. A standardized framework for the validation and verification of clinical molecular genetic tests. Eur J Hum Genet. 2010;18(12):1276–88.

    Article  PubMed Central  PubMed  Google Scholar 

  122. Jennings L, Van Deerlin VM, Gulley ML. Recommended Principles and Practices for Validating Clinical Molecular Pathology Tests. Arch Pathol Lab Med. 2009;133:743–55.

    PubMed  Google Scholar 

  123. Haas J, Katus HA, Meder B. Next-generation sequencing entering the clinical arena. Mol Cell Probes. 2011;25(5-6):206–11.

    Article  CAS  PubMed  Google Scholar 

  124. Gullapalli RR, Lyons-Weiler M, Petrosko P, et al. Clinical integration of next-generation sequencing technology. Clin Lab Med. 2012;32(4):585–99.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Kalman LV, Lubin IM, Barker S, et al. Current landscape and new paradigms of proficiency testing and external quality assessment for molecular genetics. Arch Pathol Lab Med. 2013;137(7):983–8.

    Article  PubMed Central  PubMed  Google Scholar 

  126. Schrijver I, Aziz N, Jennings LJ, et al. Methods-based proficiency testing in molecular genetic pathology. J Mol Diagn. 2014;16:283–7.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hebrew University Medical School, Jerusalem, Israel

    Rachel Michaelson-Cohen M.D. & Ephrat Levy-Lahad M.D.

  2. Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel

    Rachel Michaelson-Cohen M.D., Rachel Beeri Ph.D. & Ephrat Levy-Lahad M.D.

  3. Department of Pathology, Shaare Zedek Medical Center, Medical Genetics Institute, Jerusalem, Israel

    Eliahu Golomb M.D., Ph.D.

Authors
  1. Rachel Michaelson-Cohen M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rachel Beeri Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eliahu Golomb M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ephrat Levy-Lahad M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ephrat Levy-Lahad M.D. .

Editor information

Editors and Affiliations

  1. Pathology and Laboratory Medicine, University of Vermont College of Medicine and University of Vermont Medical Center, Burlington, Vermont, USA

    Debra G.B. Leonard

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Michaelson-Cohen, R., Beeri, R., Golomb, E., Levy-Lahad, E. (2016). Inherited Breast Cancer. In: Leonard, D. (eds) Molecular Pathology in Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-19674-9_22

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-19674-9_22

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-19673-2

  • Online ISBN: 978-3-319-19674-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation