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Familial Breast Cancer Risk

  • Risk, Prevention, and Screening (DL Hershman, Section Editor)
  • Published:
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Abstract

The most well recognized breast cancer susceptibility genes are BRCA1 and BRCA2. Studies in individuals carrying mutations in these genes have led to clinical care guidelines for screening and prevention. Beyond BRCA1 and BRCA2, mutations in TP53, PTEN, STK11, and CDH1 also significantly increase the risk of breast cancer. Early identification of women at increased risk of breast cancer due to specific genetic susceptibility may lead to enhanced screening and prevention strategies and potentially improved overall survival for this group of patients as has been seen with carriers of BRCA1 and BRCA2 mutations. In addition to high penetrance genes, increasing numbers of genes that confer a moderate risk of breast cancer have been identified such as CHEK2, PALB2, and ATM; however, the clinical application of these genes is much more challenging. This review will discuss both high and moderate penetrance breast cancer susceptibility genes.

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References

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  1. Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975–2009. Bethesda: National Cancer Institute; 2011.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  3. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med. 2008;359:2143–53.

    Article  PubMed  CAS  Google Scholar 

  4. Pharoah PD, Antoniou A, Bobrow M, et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 2002;31:33–6.

    Article  PubMed  CAS  Google Scholar 

  5. Maxwell KN, Domchek SM. Cancer treatment according to BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol. 2012;9:520–8.

    Article  PubMed  CAS  Google Scholar 

  6. Michailidou KP, Hall A, Gonzalez-Neira, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45:353–61.

    Article  PubMed  CAS  Google Scholar 

  7. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer. 2000;83:1301–8

  8. Antoniou A, Pharoah D, 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  CAS  Google Scholar 

  9. Gonzalez KD, Buzin CH, Noltner KA, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009;46:689–93.

    Article  PubMed  CAS  Google Scholar 

  10. Hwang SJ, Lozano G, Amos CI, Strong LC. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. 2003;72:975–83.

    Article  PubMed  CAS  Google Scholar 

  11. Nelen MR, Kremer H, Konings IB, et al. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. 1999;7:267–73.

    Article  PubMed  CAS  Google Scholar 

  12. Schrager CA, Schneider D, Gruener AC, et al. Clinical and pathological features of breast disease in Cowden’s syndrome: an under recognized syndrome with an increased risk of breast cancer. Hum Pathol. 1998;29:47–53.

    Article  PubMed  CAS  Google Scholar 

  13. Izatt L, Greenman J, Hodgson S, et al. Identification of germline missense mutations and rare allelic variants in the ATM gene in early-onset breast cancer. Genes Chromosomes Cancer. 1999;26:286–94.

    Article  PubMed  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39:165–7.

    Article  PubMed  CAS  Google Scholar 

  16. Seal S, Thompson D, Renwick A, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38:1239–41.

    Article  PubMed  CAS  Google Scholar 

  17. Hemel D, Domchek SM. Breast cancer predisposition syndromes. Hematol Oncol Clin North Am. 2010;24:799–814.

    Article  PubMed  Google Scholar 

  18. Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25:5864–74.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999;91:1310–6.

  21. Begg CB, Haile RW, Borg A, et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA. 2008;299:194–201.

    Article  PubMed  CAS  Google Scholar 

  22. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329–33.

    Article  PubMed  Google Scholar 

  23. • Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 Mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013. [Epub ahead of print]. This article describes results of a trial prospectively examining cancer risks in BRCA1 and BRCA2 carriers.

  24. • Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31:1748–57. This article highlights the role of identifying prostate cancer patients with BRCA1 or BRCA2 mutations. In addition, this artical strongly supports the recommendation that male members of BRCA1/2 families should undergo early prostate cancer screening.

    Article  PubMed  CAS  Google Scholar 

  25. Howlett NG, Taniguchi T, Olson S, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297:606–9.

    Article  PubMed  CAS  Google Scholar 

  26. 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  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351:427–37.

    Article  PubMed  CAS  Google Scholar 

  29. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75–89.

    Article  PubMed  Google Scholar 

  30. King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286:2251–6.

    Article  PubMed  CAS  Google Scholar 

  31. Whittemore AS, Balise RR, Pharoah PD, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer. 2004;91:1911–5.

    Article  PubMed  CAS  Google Scholar 

  32. Cibula D, Zikan M, Dusek L, Majek O. Oral contraceptives and risk of ovarian and breast cancers in BRCA mutation carriers: a meta-analysis. Expert Rev Anticancer Ther. 2011;11:1197–207.

    Article  PubMed  CAS  Google Scholar 

  33. 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;304:967–75.

    Article  PubMed  CAS  Google Scholar 

  34. Kurian AW, Sigal BM, Plevritis SK. Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol. 2010;28:222–31.

    Article  PubMed  CAS  Google Scholar 

  35. Eisen A, Lubinski J, Gronwald J, et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst. 2008;100:1361–7.

    Article  PubMed  CAS  Google Scholar 

  36. Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005;23:7804–10.

    Article  PubMed  CAS  Google Scholar 

  37. Arun B, Bayraktar S, Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol. 2011;29:3739–46.

    Article  PubMed  CAS  Google Scholar 

  38. Kriege M, Seynaeve C, Meijers-Heijboer H, et al. Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2009;27:3764–71.

    Article  PubMed  Google Scholar 

  39. Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28:375–9.

    Article  PubMed  CAS  Google Scholar 

  40. Bolton KL, Chenevix-Trench G, Goh C, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA. 2012;307:382–90.

    Article  PubMed  CAS  Google Scholar 

  41. Adams SF, Marsh EB, Elmasri W, et al. A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer. Gynecol Oncol. 2011;123:486–91.

    Article  PubMed  CAS  Google Scholar 

  42. 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;361:123–34.

    Article  PubMed  CAS  Google Scholar 

  43. Audeh MW, Penson RT, Friedlander M, Powell B, Bell-Mcguinn KM, Scott C, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer. J Clin Oncol. 2009;27:277s.

    Google Scholar 

  44. •• Kaye SB, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol. 2012;30:372–9. The effectiveness of PARP inhibitors in BRCA1/2 carriers indicates that identification of gene mutations leading to familial breast cancer may have important implications for treatment.

    Article  PubMed  CAS  Google Scholar 

  45. Tutt A, Robson M, Garber JE, 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;376:235–44.

    Article  PubMed  CAS  Google Scholar 

  46. Li FP, Fraumeni JF. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71:747–52.

    Article  PubMed  CAS  Google Scholar 

  47. Li FP, Fraumeni JF, Mulvihill Jr JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358–62.

    PubMed  CAS  Google Scholar 

  48. Frebourg T, Barbier N, Yan YX, et al. Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. Am J Hum Genet. 1995;56:608–15.

    PubMed  CAS  Google Scholar 

  49. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27:1250–6.

    Article  PubMed  CAS  Google Scholar 

  50. Varley JM, McGown G, Thorncroft M, et al. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res. 1997;57:3245–52.

    PubMed  CAS  Google Scholar 

  51. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009;458:1127–30.

    Article  PubMed  CAS  Google Scholar 

  52. Birch JM, Hartley AL, Tricker KJ, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54:1298–304.

    PubMed  CAS  Google Scholar 

  53. Chompret A, Brugieres L, Ronsin M, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82:1932–7.

    Article  PubMed  CAS  Google Scholar 

  54. Eeles RA. Germline mutations in the TP53 gene. Cancer Surv. 1995;25:101–24.

    PubMed  CAS  Google Scholar 

  55. Lalloo F, Varley J, Moran A, et al. BRCA1, BRCA2, and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer. 2006;42:1143–50.

    Article  PubMed  CAS  Google Scholar 

  56. Mouchawar J, Korch C, Byers T, et al. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res. 2010;70:4795–800.

    Article  PubMed  CAS  Google Scholar 

  57. Lee DS, Yoon SY, Looi LM, et al. Comparable frequency of BRCA1, BRCA2, and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res. 2012;14:R66.

    Article  PubMed  CAS  Google Scholar 

  58. McCuaig JM, Armel SR, Novokmet A, et al. Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer. 2012;11:607–13.

    Article  PubMed  CAS  Google Scholar 

  59. He XF, Su J, Zhang Y, et al. Association between the p53 polymorphisms and breast cancer risk: meta-analysis based on case–control study. Breast Cancer Res Treat. 2011;130:517–29.

    Article  PubMed  CAS  Google Scholar 

  60. Zhang B, Beeghly-Fadiel A, Long J, Zheng W. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011;12:477–88.

    Article  PubMed  CAS  Google Scholar 

  61. Varley JM, McGown G, Thorncroft M, et al. Are there low-penetrance TP53 Alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet. 1999;65:995–1006.

    Article  PubMed  CAS  Google Scholar 

  62. Ruijs MW, Verhoef S, Wigbout G, et al. Late-onset common cancers in a kindred with an Arg213Gln TP53 germline mutation. Fam Cancer. 2006;5:169–74.

    Article  PubMed  CAS  Google Scholar 

  63. • Giacomazzi J, Selistre S, Duarte J, et al. TP53 p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient. BMC Cancer. 2013;13:187. The identification of an individual homozygous for a TP53 mutation suggests that hypomorphic TP53 mutations may exist.

    Article  PubMed  CAS  Google Scholar 

  64. Lammens CR, Aaronson NK, Wagner A, et al. Genetic testing in Li-Fraumeni syndrome: uptake and psychosocial consequences. J Clin Oncol. 2010;28:3008–14.

    Article  PubMed  Google Scholar 

  65. Lammens CR, Bleiker EM, Aaronson NK, et al. Regular surveillance for Li-Fraumeni Syndrome: advice, adherence, and perceived benefits. Fam Cancer. 2010;9:647–54.

    Article  PubMed  CAS  Google Scholar 

  66. • Mai PL, Malkin D, Garber JE, et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. 2012;205:479–87. This report highlights the critical areas of need for additional research in the management of individuals with TP53 mutations and from LFS families.

    Article  PubMed  Google Scholar 

  67. Monsalve J, Kapur J, Malkin D, Babyn PS. Imaging of cancer predisposition syndromes in children. Radiographics. 2011;31:263–80.

    Article  PubMed  Google Scholar 

  68. Henry E, Villalobos V, Million L, et al. Chest wall leiomyosarcoma after breast-conservative therapy for early-stage breast cancer in a young woman with Li-Fraumeni syndrome. J Natl Compr Canc Netw. 2012;10:939–42.

    PubMed  Google Scholar 

  69. Salmon A, Amikam D, Sodha N, et al. Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline ‘de-novo’ TP53 mutation. Clin Oncol (R Coll Radiol). 2007;19:490–3.

    Article  PubMed  CAS  Google Scholar 

  70. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.

    Article  PubMed  CAS  Google Scholar 

  71. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.

    Article  PubMed  CAS  Google Scholar 

  72. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64–7.

    Article  PubMed  CAS  Google Scholar 

  73. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009;11:687–94.

    Article  PubMed  CAS  Google Scholar 

  74. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet. 2013;50:255–63.

    Article  PubMed  CAS  Google Scholar 

  75. • Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400–7. This article demonstrates high lifetime risks of cancers in Cowden syndrome families.

    Article  PubMed  CAS  Google Scholar 

  76. Ragaz J, Coldman A. Survival impact of adjuvant tamoxifen on competing causes of mortality in breast cancer survivors, with analysis of mortality from contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic episodes. J Clin Oncol. 1998;16:2018–24.

    PubMed  CAS  Google Scholar 

  77. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998;391:184–7.

    Article  PubMed  CAS  Google Scholar 

  78. Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998;18:38–43.

    Article  PubMed  CAS  Google Scholar 

  79. Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2:28.

    Article  PubMed  Google Scholar 

  80. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12:3209–15.

    Article  PubMed  CAS  Google Scholar 

  81. • van Lier MG, Wagner A, Mathus-Vliegen EM, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105:1258–64. This review provides extensive recommendations specifically for PJS.

    Article  PubMed  Google Scholar 

  82. Watabe M, Nagafuchi A, Tsukita S, Takeichi M. Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line. J Cell Biol. 1994;127:247–56.

    Article  PubMed  CAS  Google Scholar 

  83. Keller G, Vogelsang H, Becker I, 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;155:337–42.

    Article  PubMed  CAS  Google Scholar 

  84. 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;121:1348–53.

    Article  PubMed  CAS  Google Scholar 

  85. Schrader KA, Masciari S, Boyd N, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer. 2008;7:73–82.

    Article  PubMed  Google Scholar 

  86. Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010;47:436–44.

    Article  PubMed  CAS  Google Scholar 

  87. Hebbard PC, Macmillan A, Huntsman D, et al. Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients. Ann Surg Oncol. 2009;16:1890–5.

    Article  PubMed  CAS  Google Scholar 

  88. Masciari S, Larsson N, Senz J, et al. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet. 2007;44:726–31.

    Article  PubMed  CAS  Google Scholar 

  89. • Schrader KA, Masciari S, Boyd N, et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011;48:64–8. This article suggests that CDH1 mutations are likely not responsible for familial breast cancer alone and that families without gastric cancer are unlikely to carry CDH1 mutations.

    Article  PubMed  CAS  Google Scholar 

  90. Xie ZM, Li LS, Laquet C, et al. Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer. 2011;117:3112–7.

    Article  PubMed  CAS  Google Scholar 

  91. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.

    Article  PubMed  CAS  Google Scholar 

  92. Grandval P, Barouk-Simonet E, Bronner M, et al. Is the controversy on breast cancer as part of the Lynch-related tumor spectrum still open? Fam Cancer. 2012;11:681–3.

    Article  PubMed  Google Scholar 

  93. Dowty JG, Win AK, Buchanan DD, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat. 2013;34:490–7.

    Article  PubMed  CAS  Google Scholar 

  94. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30:958–64.

    Article  PubMed  CAS  Google Scholar 

  95. • Win AK, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res. 2013;15:R27. This article attempts to address the controversy of whether mutations in mismatch repair genes lead to increased breast cancer risk.

    Article  PubMed  CAS  Google Scholar 

  96. Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62:812–23.

    Article  PubMed  CAS  Google Scholar 

  97. Chaturvedi P, Eng WK, Zhu Y, et al. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene. 1999;18:4047–54.

    Article  PubMed  CAS  Google Scholar 

  98. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286:2528–31.

    Article  PubMed  CAS  Google Scholar 

  99. Weischer M, Bojesen SE, Tybjaerg-Hansen A, et al. Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol. 2007;25:57–63.

    Article  PubMed  CAS  Google Scholar 

  100. Weischer M, Nordestgaard BG, Pharoah P, et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol. 2012;30:4308–16.

    Article  PubMed  CAS  Google Scholar 

  101. Adank MA, Jonker MA, Kluijt I, et al. CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women. J Med Genet. 2011;48:860–3.

    Article  PubMed  CAS  Google Scholar 

  102. •• Cybulski C, Wokolorczyk D, Jakubowska A, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol. 2011;29:3747–52. This study demonstrates that the risk of breast cancer in women carrying the common CHEK2 1100delC mutation is higher in women with familial breast cancer.

    Article  PubMed  CAS  Google Scholar 

  103. Schutte M, Seal S, Barfoot R, et al. Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet. 2003;72:1023–8.

    Article  PubMed  CAS  Google Scholar 

  104. Dong X, Wang L, Taniguchi K, et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003;72:270–80.

    Article  PubMed  CAS  Google Scholar 

  105. Weischer M, Heerfordt IM, Bojesen SE, et al. CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis. J Invest Dermatol. 2012;132:299–303.

    Article  PubMed  CAS  Google Scholar 

  106. Xiang HP, Geng XP, Ge WW, Li H. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur J Cancer. 2011;47:2546–51.

    Article  PubMed  CAS  Google Scholar 

  107. Cybulski C, Gorski B, Huzarski T, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75:1131–5.

    Article  PubMed  CAS  Google Scholar 

  108. Domchek SM, Bradbury A, Garber JE, et al. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol. 2013;31:1267–70.

    Article  PubMed  Google Scholar 

  109. Xia B, Sheng Q, Nakanishi K, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22:719–29.

    Article  PubMed  CAS  Google Scholar 

  110. • Casadei S, Norquist BM, Walsh T, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011;71:2222–9. This study describes the mutational spectrum and cancer risks in families with PALB2 mutations.

    Article  PubMed  CAS  Google Scholar 

  111. Erkko H, Xia B, Nikkila J, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007;446:316–9.

    Article  PubMed  CAS  Google Scholar 

  112. Foulkes WD, Ghadirian P, Akbari MR, et al. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 2007;9:R83.

    Article  PubMed  CAS  Google Scholar 

  113. Reid S, Schindler D, Hanenberg H, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39:162–4.

    Article  PubMed  CAS  Google Scholar 

  114. Xia B, Dorsman JC, Ameziane N, et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet. 2007;39:159–61.

    Article  PubMed  CAS  Google Scholar 

  115. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217.

    Article  PubMed  CAS  Google Scholar 

  116. Hofstatter EW, Domchek SM, Miron A, et al. PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 2011;10:225–31.

    Article  PubMed  CAS  Google Scholar 

  117. Savitsky K, Sfez S, Tagle DA, et al. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet. 1995;4:2025–32.

    Article  PubMed  CAS  Google Scholar 

  118. Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst. 1986;77:89–92.

    PubMed  CAS  Google Scholar 

  119. Bhatti S, Kozlov S, Farooqi AA, et al. ATM protein kinase: the linchpin of cellular defenses to stress. Cell Mol Life Sci. 2011;68:2977–3006.

    Article  PubMed  CAS  Google Scholar 

  120. Athma P, Rappaport R, Swift M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet. 1996;92:130–4.

    Article  PubMed  CAS  Google Scholar 

  121. FitzGerald MG, Bean JM, Hegde SR, et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet. 1997;15:307–10.

    Article  PubMed  CAS  Google Scholar 

  122. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38:873–5.

    Article  PubMed  CAS  Google Scholar 

  123. Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005;97:813–22.

    Article  PubMed  CAS  Google Scholar 

  124. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6.

    Article  PubMed  CAS  Google Scholar 

  125. Fletcher O, Johnson N, dos Santos SI, et al. Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls. Cancer Epidemiol Biomarkers Prev. 2010;19:2143–51.

    Article  PubMed  CAS  Google Scholar 

  126. • Tavtigian SV, Oefner PJ, Babikyan D, et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009;85:427–46. This article importantly describes the types of missense mutations, which may be associated with ataxia telangiectasia when homozygous and breast cancer when heterozgyous.

    Article  PubMed  CAS  Google Scholar 

  127. Feigin RD, Vietti TJ, Wyatt RG, et al. Ataxia telangiectasia with granulocytopenia. J Pediatr. 1970;77:431–8.

    Article  PubMed  CAS  Google Scholar 

  128. Briani C, Schlotter M, Lichter P, Kalla C. Development of a mantle cell lymphoma in an ATM heterozygous woman after occupational exposure to ionising radiation and somatic mutation of the second allele. Leuk Res. 2006;30:1193–6.

    Article  PubMed  Google Scholar 

  129. Bernstein JL, Haile RW, Stovall M, et al. Radiation exposure, the ATM Gene, and contralateral breast cancer in the women’s environmental cancer and radiation epidemiology study. J Natl Cancer Inst. 2010;102:475–83.

    Article  PubMed  CAS  Google Scholar 

  130. Meyer A, John E, Dork T, et al. Breast cancer in female carriers of ATM gene alterations: outcome of adjuvant radiotherapy. Radiother Oncol. 2004;72:319–23.

    Article  PubMed  CAS  Google Scholar 

  131. Bremer M, Klopper K, Yamini P, et al. Clinical radiosensitivity in breast cancer patients carrying pathogenic ATM gene mutations: no observation of increased radiation-induced acute or late effects. Radiother Oncol. 2003;69:155–60.

    Article  PubMed  CAS  Google Scholar 

  132. Levitus M, Waisfisz Q, Godthelp BC, et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005;37:934–5.

    Article  PubMed  CAS  Google Scholar 

  133. Levran O, Attwooll C, Henry RT, et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet. 2005;37:931–3.

    Article  PubMed  CAS  Google Scholar 

  134. Rafnar T, Gudbjartsson DF, Sulem P, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011;43:1104–7.

    Article  PubMed  CAS  Google Scholar 

  135. Bartkova J, Tommiska J, Oplustilova L, 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;2:296–316.

    Article  PubMed  Google Scholar 

  136. Heikkinen K, Rapakko K, Karppinen SM, et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis. 2006;27:1593–9.

    Article  PubMed  CAS  Google Scholar 

  137. Tommiska J, Seal S, Renwick A, et al. Evaluation of RAD50 in familial breast cancer predisposition. Int J Cancer. 2006;118:2911–6.

    Article  PubMed  CAS  Google Scholar 

  138. Stewart GS, Maser RS, Stankovic T, et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell. 1999;99:577–87.

    Article  PubMed  CAS  Google Scholar 

  139. Varon R, Vissinga C, Platzer M, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998;93:467–76.

    Article  PubMed  CAS  Google Scholar 

  140. Waltes R, Kalb R, Gatei M, et al. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet. 2009;84:605–16.

    Article  PubMed  CAS  Google Scholar 

  141. 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;42:410–4.

    Article  PubMed  CAS  Google Scholar 

  142. Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43:879–82.

    Article  PubMed  CAS  Google Scholar 

  143. Thompson ER, Boyle SE, Johnson J, et al. Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat. 2012;33:95–9.

    Article  PubMed  CAS  Google Scholar 

  144. Thompson ER, Rowley SM, Sawyer S, et al. Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS One. 2013;8:e54772.

    Article  PubMed  CAS  Google Scholar 

  145. Vaz F, Hanenberg H, Schuster B, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42:406–9.

    Article  PubMed  CAS  Google Scholar 

  146. •• Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28:893–901. This article describes the most recent ASCO guidelines regarding germline testing for cancer susceptibility.

    Article  PubMed  Google Scholar 

  147. Shannon KM, Chittenden A. Genetic testing by cancer site: breast. Cancer J. 2012;18:310–9.

    Article  PubMed  Google Scholar 

  148. Shendure J, Aiden EL. The expanding scope of DNA sequencing. Nat Biotechnol. 2012;30:1084–94.

    Article  PubMed  CAS  Google Scholar 

  149. Biesecker LG, Burke W, Kohane I, et al. Next-generation sequencing in the clinic: are we ready? Nat Rev Genet. 2012;13:818–24.

    Article  PubMed  CAS  Google Scholar 

  150. Kohlmann A, Grossmann V, Haferlach T. Integration of next-generation sequencing into clinical practice: are we there yet? Semin Oncol. 2012;39:26–36.

    Article  PubMed  CAS  Google Scholar 

  151. Gopie JP, Mureau MA, Seynaeve C, et al. Body image issues after bilateral prophylactic mastectomy with breast reconstruction in healthy women at risk for hereditary breast cancer. Fam Cancer. 2012;[Epub ahead of print]

  152. Gahm J, Wickman M, Brandberg Y. Bilateral prophylactic mastectomy in women with inherited risk of breast cancer–prevalence of pain and discomfort, impact on sexuality, quality of life and feelings of regret 2 years after surgery. Breast. 2010;19:462–9.

    Article  PubMed  Google Scholar 

  153. Zendejas B, Moriarty JP, O’Byrne J, et al. Cost-effectiveness of contralateral prophylactic mastectomy vs routine surveillance in patients with unilateral breast cancer. J Clin Oncol. 2011;29:2993–3000.

    Article  PubMed  Google Scholar 

  154. Easton DF, Deffenbaugh AM, Pruss D, et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007;81:873–83.

    Article  PubMed  CAS  Google Scholar 

  155. Guidugli L, Pankratz VS, Singh N, et al. A classification model for BRCA2 DNA binding domain missense variants based on homology directed repair activity. Cancer Res. 2013;73:265–75.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Kara N. Maxwell receives funding from National Institutes of Health (2T32GM008638-16). Susan M. Domchek receives funding from the Basser Research Center for BRCA, Breast Cancer Research Foundation, and Susan G. Komen for the Cure.

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Kara N. Maxwell declares no conflict of interest.

Susan M. Domchek declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Division of Hematology/Oncology, Department of Internal Medicine, University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, PA, 19104, USA

    Kara N. Maxwell

  2. Abramson Cancer Center, Department of Internal Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, 3 West Perelman Center, Philadelphia, PA, 19104, USA

    Susan M. Domchek

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  1. Kara N. Maxwell
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Correspondence to Susan M. Domchek.

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Maxwell, K.N., Domchek, S.M. Familial Breast Cancer Risk. Curr Breast Cancer Rep 5, 170–182 (2013). https://doi.org/10.1007/s12609-013-0117-9

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