Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Hereditary breast and ovarian cancer: new genes in confined pathways

Key Points

  • Genetic abnormalities in BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of HBOC cases can be ascribed to BRCA1 and BRCA2 mutations.

  • Next-generation sequencing approaches are uncovering novel HBOC factors among affected families without BRCA1 or BRCA2 mutations; at present more than 25 have emerged. New factors generally function in the same genome maintenance pathways as established HBOC factors, indicating substantial locus heterogeneity.

  • Disabled pathways in HBOC are homologous recombination repair (HRR), protection of stalling DNA replication forks, mismatch repair, and cell cycle checkpoint and DNA damage checkpoint control pathways.

  • The new pathogenic variants are rare, which poses challenges to the estimation of risk attribution through patient cohorts. There is a risk that patients or healthy carriers exhibiting pathogenic variants in rare HBOC genes may be excluded from the best possible treatment or presymptomatic screening programmes.

  • Structural and functional analysis can support variant classification in the context of international collaboration and standardized guidelines. Functional approaches are aided by extensive locus heterogeneity, which converges on a relatively small number of genome maintenance pathways that may be reconciled in vitro.

Abstract

Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts. In this Review article, we examine HBOC genes, focusing on their role in genome maintenance, the possibilities for functional testing of putative causal variants and the clinical application of new HBOC genes in cancer risk management and treatment decision-making.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Timeline of events important in HBOC discovery and the identification of predisposing HBOC genes.
Figure 2: Tumour suppression requires functional genome maintenance pathways to counteract genotoxic stress cues.
Figure 3: Genome stability pathways and genes in HBOC.
Figure 4: Proposed clinical management of breast and ovarian tumours.

Similar content being viewed by others

References

  1. Broca, P. Traité des Tumeurs (ed. Asselin, P.) (Paris, 1866).

    Google Scholar 

  2. Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).

    PubMed  PubMed Central  Google Scholar 

  3. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).This study describes the mapping of the BRCA1 gene.

    CAS  PubMed  Google Scholar 

  4. Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).This study describes the mapping of the BRCA2 gene.

    CAS  PubMed  Google Scholar 

  5. Antoniou, A. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen, S. & Parmigiani, G. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin. Oncol. 25, 1329–1333 (2007).

    PubMed  Google Scholar 

  7. Mavaddat, N. et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J. Natl Cancer Inst. 105, 812–822 (2013).

    CAS  PubMed  Google Scholar 

  8. Tai, Y. C., Domchek, S., Parmigiani, G. & Chen, S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J. Natl Cancer Inst. 99, 1811–1814 (2007).

    CAS  PubMed  Google Scholar 

  9. Campeau, P. M., Foulkes, W. D. & Tischkowitz, M. D. Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum. Genet. 124, 31–42 (2008).

    CAS  PubMed  Google Scholar 

  10. Walsh, T. et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc. Natl Acad. Sci. USA 108, 18032–18037 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kast, K. et al. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. J. Med. Genet. 3, 465–471 (2016).

    Google Scholar 

  12. Cybulski, C. et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat. Genet. 47, 643–646 (2015).

    CAS  PubMed  Google Scholar 

  13. Park, D. J. et al. Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers. Cancer Discov. 4, 804–815 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Sun, J. et al. Mutations in RECQL gene are associated with predisposition to breast cancer. PLoS Genet. 11, e1005228 (2015).

    PubMed  PubMed Central  Google Scholar 

  15. Easton, D. F. et al. Gene-panel sequencing and the prediction of breast-cancer risk. N. Engl. J. Med. 372, 2243–2257 (2015).This review summarizes the current knowledge of HBOC genes included in gene panels in relation to their estimated breast cancer risk.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Shiovitz, S. & Korde, L. A. Genetics of breast cancer: a topic in evolution. Ann. Oncol. 26, 1291–1299 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Santos-Pereira, J. M. & Aguilera, A. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583–597 (2015).

    CAS  PubMed  Google Scholar 

  18. Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).This paper identifies a new role of BRCA2 in promoting DNA replication fork stability.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Prakash, R., Zhang, Y., Feng, W. & Jasin, M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb. Perspect. Biol. 7, a016600 (2015).

    PubMed  PubMed Central  Google Scholar 

  20. Lavin, M. F., Kozlov, S., Gatei, M. & Kijas, A. W. ATM-dependent phosphorylation of all three members of the MRN complex: from sensor to adaptor. Biomolecules 5, 2877–2902 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Paull, T. T. Mechanisms of ATM Activation. Annu. Rev. Biochem. 84, 711–738 (2015).

    CAS  PubMed  Google Scholar 

  22. Stracker, T. H. & Petrini, J. H. The MRE11 complex: starting from the ends. Nat. Rev. Mol. Cell Biol. 12, 90–103 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, H. et al. The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair. PLoS Genet. 9, e1003277 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu, J., Doty, T., Gibson, B. & Heyer, W. D. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat. Struct. Mol. Biol. 17, 1260–1262 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jensen, R. B., Carreira, A. & Kowalczykowski, S. C. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467, 678–683 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Thorslund, T. et al. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 17, 1263–1265 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Jiang, Q. & Greenberg, R. A. Deciphering the BRCA1 tumor suppressor network. J. Biol. Chem. 290, 17724–17732 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Roy, R., Chun, J. & Powell, S. N. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat. Rev. Cancer 12, 68–78 (2012).

    CAS  Google Scholar 

  29. Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bothmer, A. et al. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J. Exp. Med. 207, 855–865 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cao, L. et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol. Cell 35, 534–541 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–U656 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  34. Bogdanova, N. et al. NBS1 variant I171V and breast cancer risk. Breast Cancer Res. Treat. 112, 75–79 (2008).

    CAS  PubMed  Google Scholar 

  35. Damiola, F. et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case–control mutation-screening study. Breast Cancer Res. 16, R58 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. Pennington, K. P. et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin. Cancer Res. 20, 764–775 (2014).

    CAS  PubMed  Google Scholar 

  37. Ramus, S. J. et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J. Natl Cancer Inst. 107, djv214 (2015).

    PubMed  PubMed Central  Google Scholar 

  38. Goldgar, D. E. et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 13, R73 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Renwick, A. et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 38, 873–875 (2006).

    CAS  PubMed  Google Scholar 

  40. Van Os, N. J. et al. Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin. Genet. https://dx.doi.org/10.1111/cge.12710 (2015).

  41. Grigaravicius, P. et al. Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain. Cell Death Differ. 23, 454–468 (2016).

    CAS  PubMed  Google Scholar 

  42. Lin, X. et al. RINT-1 serves as a tumor suppressor and maintains Golgi dynamics and centrosome integrity for cell survival. Mol. Cell. Biol. 27, 4905–4916 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Shakya, R. et al. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc. Natl Acad. Sci. USA 105, 7040–7045 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Lee, C. et al. Functional analysis of BARD1 missense variants in homology-directed repair of DNA double strand breaks. Hum. Mutat. 36, 1205–1214 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Westermark, U. K. et al. BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks. Mol. Cell. Biol. 23, 7926–7936 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, F. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).

    CAS  PubMed  Google Scholar 

  48. Buisson, R. et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat. Struct. Mol. Biol. 17, 1247–1254 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ahlskog, J. K., Larsen, B. D., Achanta, K. & Sorensen, C. S. ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function. EMBO Rep. 17, 671–681 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Orthwein, A. et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature 528, 422–426 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Suwaki, N., Klare, K. & Tarsounas, M. RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin. Cell Dev. Biol. 22, 898–905 (2011).

    CAS  PubMed  Google Scholar 

  52. De Brakeleer, S. et al. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum. Mutat. 31, E1175–E1185 (2010).

    CAS  PubMed  Google Scholar 

  53. Erkko, H. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007).

    CAS  PubMed  Google Scholar 

  54. Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 39, 165–167 (2007).

    CAS  PubMed  Google Scholar 

  55. Golmard, L. et al. Germline mutation in the RAD51B gene confers predisposition to breast cancer. BMC Cancer 13, 484 (2013).

    PubMed  PubMed Central  Google Scholar 

  56. Song, H. et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J. Clin. Oncol. 33, 2901–2907 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Jonson, L. et al. Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer. Breast Cancer Res. Treat. 155, 215–222 (2016).

    PubMed  Google Scholar 

  58. Loveday, C. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat. Genet. 43, 879–882 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Meindl, A. et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Genet. 42, 410–414 (2010).

    CAS  PubMed  Google Scholar 

  60. Sopik, V., Akbari, M. R. & Narod, S. A. Genetic testing for RAD51C mutations: in the clinic and community. Clin. Genet. 88, 303–312 (2015).

    CAS  PubMed  Google Scholar 

  61. Baker, J. L., Schwab, R. B., Wallace, A. M. & Madlensky, L. Breast cancer in a RAD51D mutation carrier: case report and review of the literature. Clin. Breast Cancer 15, e71–75 (2015).

    PubMed  Google Scholar 

  62. Park, D. J. et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am. J. Hum. Genet. 90, 734–739 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hilbers, F. S. et al. Rare variants in XRCC2 as breast cancer susceptibility alleles. J. Med. Genet. 49, 618–620 (2012).

    CAS  PubMed  Google Scholar 

  64. Seal, S. et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 38, 1239–1241 (2006).

    CAS  PubMed  Google Scholar 

  65. Easton, D. F. et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J. Med. Genet. 53, 298–309 (2016).

    CAS  PubMed  Google Scholar 

  66. Rafnar, T. et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat. Genet. 43, 1104–1107 (2011).

    CAS  PubMed  Google Scholar 

  67. Solyom, S. et al. Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions. Sci. Transl Med. 4, 122ra23 (2012).

    PubMed  Google Scholar 

  68. Schlacher, K., Wu, H. & Jasin, M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22, 106–116 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Sharan, S. K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).

    CAS  PubMed  Google Scholar 

  70. Chaudhuri, A. R. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535, 382–387 (2016).

    CAS  PubMed Central  Google Scholar 

  71. Murphy, A. K. et al. Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery. J. Cell Biol. 206, 493–507 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Nikkila, J. et al. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nat. Commun. 4, 2578 (2013).

    PubMed  Google Scholar 

  73. Pathania, S. et al. BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat. Commun. 5, 5496 (2014).

    PubMed  Google Scholar 

  74. Sedic, M. et al. Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat. Commun. 6, 7505 (2015).

    CAS  PubMed  Google Scholar 

  75. Jeng, Y. M. et al. Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene 26, 6160–6166 (2007).

    CAS  PubMed  Google Scholar 

  76. Croteau, D. L., Popuri, V., Opresko, P. L. & Bohr, V. A. Human RecQ helicases in DNA repair, recombination, and replication. Annu. Rev. Biochem. 83, 519–552 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Bogliolo, M. & Surralles, J. Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Curr. Opin. Genet. Dev. 33, 32–40 (2015).

    CAS  PubMed  Google Scholar 

  78. Kiiski, J. I. et al. Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proc. Natl Acad. Sci. USA 111, 15172–15177 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Thompson, E. R. et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 8, e1002894 (2012).This is the first description of the use of exome sequencing data in the identification of putative novel HBOC genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bogdanova, N. et al. Prevalence of the BLM nonsense mutation, Q548X, in ovarian cancer patients from Central and Eastern Europe. Fam. Cancer 14, 145–149 (2015).

    CAS  PubMed  Google Scholar 

  81. Solyom, S. et al. Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family. Cancer Lett. 302, 113–118 (2011).

    CAS  PubMed  Google Scholar 

  82. Ellingson, M. S. et al. Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. Breast Cancer Res. Treat. 153, 435–443 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Gardini, A., Baillat, D., Cesaroni, M. & Shiekhattar, R. Genome-wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co-activation. EMBO J. 33, 890–905 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gorski, J. J. et al. Profiling of the BRCA1 transcriptome through microarray and ChIP-chip analysis. Nucleic Acids Res. 39, 9536–9548 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Bhatia, V. et al. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511, 362–365 (2014).Identifies a new role for BRCA2 in preventing transcription-induced stress at the replication fork.

    CAS  PubMed  Google Scholar 

  86. Hatchi, E. et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57, 636–647 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Garcia-Rubio, M. L. et al. The Fanconi anemia pathway protects genome integrity from R-loops. PLoS Genet. 11, e1005674 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. Pena-Diaz, J. & Jiricny, J. Mammalian mismatch repair: error-free or error-prone? Trends Biochem. Sci. 37, 206–214 (2012).

    CAS  PubMed  Google Scholar 

  89. Vasen, H. F., Tomlinson, I. & Castells, A. Clinical management of hereditary colorectal cancer syndromes. Nat. Rev. Gastroenterol. Hepatol 12, 88–97 (2015).

    PubMed  Google Scholar 

  90. Bonadona, V. et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305, 2304–2310 (2011).

    CAS  PubMed  Google Scholar 

  91. Engel, C. et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J. Clin. Oncol. 30, 4409–4415 (2012).

    PubMed  Google Scholar 

  92. Harkness, E. F. et al. Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study. J. Med. Genet. 52, 553–556 (2015).

    CAS  PubMed  Google Scholar 

  93. ten Broeke, S. W. et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J. Clin. Oncol. 33, 319–325 (2015).

    PubMed  Google Scholar 

  94. Alemayehu, A. & Fridrichova, I. The MRE11/RAD50/NBS1 complex destabilization in Lynch-syndrome patients. Eur. J. Hum. Genet. 15, 922–929 (2007).

    CAS  PubMed  Google Scholar 

  95. de Wind, N., Dekker, M., Berns, A., Radman, M. & te Riele, H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82, 321–330 (1995).

    CAS  PubMed  Google Scholar 

  96. Tham, K. C., Kanaar, R. & Lebbink, J. H. Mismatch repair and homeologous recombination. DNA Repair (Amst.) 38, 75–83 (2016).

    CAS  Google Scholar 

  97. Shiloh, Y. ATM: expanding roles as a chief guardian of genome stability. Exp. Cell Res. 329, 154–161 (2014).

    CAS  PubMed  Google Scholar 

  98. Smith, J., Tho, L. M., Xu, N. & Gillespie, D. A. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv. Cancer Res. 108, 73–112 (2010).

    CAS  PubMed  Google Scholar 

  99. Zilfou, J. T. & Lowe, S. W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol. 1, a001883 (2009).

    PubMed  PubMed Central  Google Scholar 

  100. Fabbro, M. et al. BRCA1–BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. J. Biol. Chem. 279, 31251–31258 (2004).

    CAS  PubMed  Google Scholar 

  101. Shaltiel, I. A., Krenning, L., Bruinsma, W. & Medema, R. H. The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle. J. Cell Sci. 128, 607–620 (2015).

    CAS  PubMed  Google Scholar 

  102. McBride, K. A. et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat. Rev. Clin. Oncol. 11, 260–271 (2014).

    CAS  PubMed  Google Scholar 

  103. Gonzalez, K. D. et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J. Clin. Oncol. 27, 1250–1256 (2009).

    CAS  PubMed  Google Scholar 

  104. Canman, C. E. et al. Activation of the ATM kinase by ionising radiation and phosphorylation of p53. Science 281, 1677–1679 (1998).

    CAS  PubMed  Google Scholar 

  105. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).

    CAS  PubMed  Google Scholar 

  106. Guo, Y., Feng, W., Sy, S. M. & Huen, M. S. ATM-dependent phosphorylation of the Fanconi anemia protein PALB2 promotes the DNA damage response. J. Biol. Chem. 290, 27545–27556 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).

    CAS  PubMed  Google Scholar 

  108. Meijers-Heijboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet. 31, 55–59 (2002).

    CAS  PubMed  Google Scholar 

  109. Weischer, M. 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. 30, 4308–4316 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Huijts, P. E. et al. CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer. Eur. J. Hum. Genet. 22, 46–51 (2014).

    CAS  PubMed  Google Scholar 

  111. Hartmann, L. C. & Lindor, N. M. The Role of risk-reducing surgery in hereditary breast and ovarian cancer. N. Engl. J. Med. 374, 454–468 (2016).

    CAS  PubMed  Google Scholar 

  112. Sestak, I. & Cuzick, J. Update on breast cancer risk prediction and prevention. Curr. Opin. Obstet. Gynecol. 27, 92–97 (2015).

    PubMed  Google Scholar 

  113. Cuzick, J. et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 361, 296–300 (2003).

    CAS  PubMed  Google Scholar 

  114. King, M. C. 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 286, 2251–2256 (2001).

    CAS  PubMed  Google Scholar 

  115. Nichols, H. B., DeRoo, L. A., Scharf, D. R. & Sandler, D. P. Risk–benefit profiles of women using tamoxifen for chemoprevention. J. Natl Cancer Inst. 107, 354 (2015).

    PubMed  Google Scholar 

  116. Cuzick, J. et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383, 1041–1048 (2014).

    CAS  PubMed  Google Scholar 

  117. Tan, D. S. et al. “BRCAness” syndrome in ovarian cancer: a case–control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J. Clin. Oncol. 26, 5530–5536 (2008).

    PubMed  Google Scholar 

  118. Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. https://dx.doi.org/10.1158/1078-0432.CCR-15-2477 (2016).

  119. Gadducci, A. & Guerrieri, M. E. PARP inhibitors in epithelial ovarian cancer: state of art and perspectives of clinical research. Anticancer Res. 36, 2055–2064 (2016).

    CAS  PubMed  Google Scholar 

  120. Rebbeck, T. R. et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313, 1347–1361 (2015).This study describes the risk of breast or ovarian cancer in relation to type and location of BRCA1 and BRCA2 mutations.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Jhuraney, A. et al. BRCA1 Circos: a visualisation resource for functional analysis of missense variants. J. Med. Genet. 52, 224–230 (2015).

    CAS  PubMed  Google Scholar 

  122. Plon, S. E. et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum. Mutat. 29, 1282–1291 (2008).This study describes the recommendations for a common classification system for variants in predisposing cancer genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Spurdle, A. B. 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 BRCA1 and BRCA2 genes. Hum. Mutat. 33, 2–7 (2012).

    CAS  PubMed  Google Scholar 

  124. Complexo et al. COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration. Breast Cancer Res. 15, 402 (2013).

  125. Eccles, D. M. et al. BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Ann. Oncol. 26, 2057–2065 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Mooney, S. D. & Klein, T. E. The functional importance of disease-associated mutation. BMC Bioinformatics 3, 24 (2002).

    PubMed  PubMed Central  Google Scholar 

  127. Dixit, A., Torkamani, A., Schork, N. J. & Verkhivker, G. Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability. Biophys. J. 96, 858–874 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Gkeka, P. et al. Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant. PLoS Comput. Biol. 10, e1003895 (2014).

    PubMed  PubMed Central  Google Scholar 

  129. Lu, S., Jang, H., Nussinov, R. & Zhang, J. The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B. Sci. Rep. 6, 21949 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Martin, A. C. et al. Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein. Hum. Mutat. 19, 149–164 (2002).

    CAS  PubMed  Google Scholar 

  131. Lim, K. H., Ferraris, L., Filloux, M. E., Raphael, B. J. & Fairbrother, W. G. Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc. Natl Acad. Sci. USA 108, 11093–11098 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sterne-Weiler, T., Howard, J., Mort, M., Cooper, D. N. & Sanford, J. R. Loss of exon identity is a common mechanism of human inherited disease. Genome Res. 21, 1563–1571 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Vallee, M. P. et al. Adding in silico assessment of potential splice aberration to the integrated evaluation of BRCA gene unclassified variants. Hum. Mutat. 37, 627–639 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Steffensen, A. Y. et al. Functional characterization of BRCA1 gene variants by mini-gene splicing assay. Eur. J. Hum. Genet. 22, 1362–1368 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Colombo, M. et al. Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. Hum. Mol. Genet. 23, 3666–3680 (2014).

    CAS  PubMed  Google Scholar 

  136. Fackenthal, J. D. et al. Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples. J. Med. Genet. https://dx.doi.org/10.1136/jmedgenet-2015-103570 (2016).

  137. de la Hoya, M. et al. Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Hum. Mol. Genet. https://dx.doi.org/10.1093/hmg/ddw094 (2016).

  138. Guidugli, L. et al. Functional assays for analysis of variants of uncertain significance in BRCA2. Hum. Mutat. 35, 151–164 (2014).This paper reviews the methods used for functional analysis of BRCA2 variants.

    CAS  PubMed  Google Scholar 

  139. Millot, G. A. et al. A guide for functional analysis of BRCA1 variants of uncertain significance. Hum. Mutat. 33, 1526–1537 (2012).This paper reviews the methods used for functional analysis of BRCA1 variants.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Starita, L. M. et al. Massively parallel functional analysis of BRCA1 RING domain variants. Genetics 200, 413–422 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Reid, L. J. et al. E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks. Proc. Natl Acad. Sci. USA 105, 20876–20881 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Shakya, R. et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334, 525–528 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Guidugli, L. et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 73, 265–275 (2013).

    CAS  PubMed  Google Scholar 

  144. Loke, J. et al. Functional variant analyses (FVAs) predict pathogenicity in the BRCA1 DNA double-strand break repair pathway. Hum. Mol. Genet. 24, 3030–3037 (2015).

    CAS  PubMed  Google Scholar 

  145. Biswas, K. et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood 118, 2430–2442 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Biswas, K. et al. Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. Hum. Mol. Genet. 21, 3993–4006 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Bouwman, P. et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 3, 1142–1155 (2013).

    CAS  PubMed  Google Scholar 

  148. Chang, S., Biswas, K., Martin, B. K., Stauffer, S. & Sharan, S. K. Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations. J. Clin. Invest. 119, 3160–3171 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Kuznetsov, S. G., Liu, P. & Sharan, S. K. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat. Med. 14, 875–881 (2008).This study describes the use of a stem cell-based assay to examine BRCA2 variants.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).

    CAS  PubMed  Google Scholar 

  151. Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Woods, N. T. et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. Genom. Med. https://dx.doi.org/10.1038/npjgenmed.2016.1 (2016).

  153. Drost, M. et al. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome. Proc. Natl Acad. Sci. USA 110, 9403–9408 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Hennessy, B. T., Coleman, R. L. & Markman, M. Ovarian cancer. Lancet 374, 1371–1382 (2009).

    CAS  PubMed  Google Scholar 

  155. Narod, S. A. Breast cancer in young women. Nat. Rev. Clin. Oncol. 9, 460–470 (2012).

    CAS  PubMed  Google Scholar 

  156. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350, 1047–1059 (1997).

  157. Lacey, J. V. Jr et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288, 334–341 (2002).

    CAS  PubMed  Google Scholar 

  158. Rodriguez, C., Patel, A. V., Calle, E. E., Jacob, E. J. & Thun, M. J. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285, 1460–1465 (2001).

    CAS  PubMed  Google Scholar 

  159. Kurman, R. J. & Shih, I. E. M. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am. J. Pathol. 186, 733–747 (2016).

    PubMed  PubMed Central  Google Scholar 

  160. Narod, S. A. et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J. Natl Cancer Inst. 94, 1773–1779 (2002).

    CAS  PubMed  Google Scholar 

  161. Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Guedj, M. et al. A refined molecular taxonomy of breast cancer. Oncogene 31, 1196–1206 (2012).

    CAS  PubMed  Google Scholar 

  163. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  PubMed  Google Scholar 

  164. Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Prat, A. et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast 24 (Suppl. 2), S26–S35 (2015).

    PubMed  Google Scholar 

  166. Van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  PubMed  Google Scholar 

  167. Farmer, P. et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24, 4660–4671 (2005).

    CAS  PubMed  Google Scholar 

  168. Prat, A. et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12, R68 (2010).

    PubMed  PubMed Central  Google Scholar 

  169. Jonsson, G. et al. The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer. Cancer Res. 72, 4028–4036 (2012).

    PubMed  Google Scholar 

  170. Larsen, M. J. et al. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling. PLoS ONE 8, e64268 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).This paper reviews the molecular features of BRCA-mutant tumours, the biomarkers used to identify BRCAness and BRCAness in relation to treatment with PARP inhibitors and platinum therapy.

    CAS  PubMed  Google Scholar 

  172. Patch, A. M. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).

    CAS  PubMed  Google Scholar 

  173. Peng, G. et al. Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat. Commun. 5, 3361 (2014).

    PubMed  Google Scholar 

  174. Timms, K. M. et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 16, 475 (2014).

    PubMed  PubMed Central  Google Scholar 

  175. Naipal, K. A. et al. Functional ex vivo assay to select homologous recombination-deficient breast tumors for PARP inhibitor treatment. Clin. Cancer Res. 20, 4816–4826 (2014).

    CAS  PubMed  Google Scholar 

  176. Morganella, S. et al. The topography of mutational processes in breast cancer genomes. Nat. Commun. 7, 11383 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Corso, G., Intra, M., Trentin, C., Veronesi, P. & Galimberti, V. CDH1 germline mutations and hereditary lobular breast cancer. Fam. Cancer 15, 215–219 (2016).

    CAS  PubMed  Google Scholar 

  179. Guilford, P. J. et al. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum. Mutat. 14, 249–255 (1999).

    CAS  PubMed  Google Scholar 

  180. Hansford, S. et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 1, 23–32 (2015).

    PubMed  Google Scholar 

  181. Benusiglio, P. R. et al. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J. Med. Genet. 50, 486–489 (2013).

    CAS  PubMed  Google Scholar 

  182. Petridis, C. et al. Germline CDH1 mutations in bilateral lobular carcinoma in situ. Br. J. Cancer 110, 1053–1057 (2014).

    CAS  PubMed  Google Scholar 

  183. Ratner, N. & Miller, S. J. A. RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat. Rev. Cancer 15, 290–301 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Seminog, O. O. & Goldacre, M. J. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br. J. Cancer 108, 193–198 (2013).

    CAS  PubMed  Google Scholar 

  185. Sharif, S. et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J. Med. Genet. 44, 481–484 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Seminog, O. O. & Goldacre, M. J. Age-specific risk of breast cancer in women with neurofibromatosis type 1. Br. J. Cancer 112, 1546–1548 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Pulido, R. PTEN: a yin-yang master regulator protein in health and disease. Methods 77–78, 3–10 (2015).

    PubMed  Google Scholar 

  188. Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16, 64–67 (1997).

    CAS  PubMed  Google Scholar 

  189. Leslie, N. R. & Longy, M. Inherited PTEN mutations and the prediction of phenotype. Semin. Cell Dev. Biol. 52, 30–38 (2016).

    CAS  PubMed  Google Scholar 

  190. Tan, M. H. et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 18, 400–407 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).

    CAS  PubMed  Google Scholar 

  192. Fraser, M. et al. PTEN deletion in prostate cancer cells does not associate with loss of RAD51 function: implications for radiotherapy and chemotherapy. Clin. Cancer Res. 18, 1015–1027 (2012).

    CAS  PubMed  Google Scholar 

  193. Gupta, A. et al. Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle 8, 2198–2210 (2009).

    CAS  PubMed  Google Scholar 

  194. McEllin, B. et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 70, 5457–5464 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. McCabe, N. et al. Mechanistic rationale to target PTEN-deficient tumor cells with inhibitors of the DNA damage response kinase ATM. Cancer Res. 75, 2159–2165 (2015).

    CAS  PubMed  Google Scholar 

  196. Momcilovic, M. & Shackelford, D. B. Targeting LKB1 in cancer - exposing and exploiting vulnerabilities. Br. J. Cancer 113, 574–584 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998).

    CAS  PubMed  Google Scholar 

  198. Beggs, A. D. et al. Peutz–Jeghers syndrome: a systematic review and recommendations for management. Gut 59, 975–986 (2010).

    CAS  PubMed  Google Scholar 

  199. Lim, W. et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126, 1788–1794 (2004).

    CAS  PubMed  Google Scholar 

  200. Gupta, R., Liu, A. Y., Glazer, P. M. & Wajapeyee, N. LKB1 preserves genome integrity by stimulating BRCA1 expression. Nucleic Acids Res. 43, 259–271 (2015).

    CAS  PubMed  Google Scholar 

  201. Sanger, F., Nicklen, S. & Coulson, A. R. DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA 74, 5463–5467 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

    CAS  PubMed  Google Scholar 

  203. Watson, P. & Lynch, H. T. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71, 677–685 (1993).

    CAS  PubMed  Google Scholar 

  204. Athma, P., Rappaport, R. & Swift, M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet. Cytogenet. 92, 130–134 (1996).

    CAS  PubMed  Google Scholar 

  205. Schaner, M. E. et al. Gene expression patterns in ovarian carcinomas. Mol. Biol. Cell 14, 4376–4386 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Gorski, B. et al. Germline 657del5 mutation in the NBS1 gene in breast cancer patients. Int. J. Cancer 106, 379–381 (2003).

    CAS  PubMed  Google Scholar 

  207. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    CAS  PubMed  Google Scholar 

  208. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).These two studies describe the effects of PARP inhibition on BRCA-deficient cells.

    CAS  PubMed  Google Scholar 

  209. Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Weischer, M., Bojesen, S. E., Ellervik, C., Tybjaerg-Hansen, A. & Nordestgaard, B. G. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J. Clin. Oncol. 26, 542–548 (2008).

    PubMed  Google Scholar 

  211. Antoniou, A. C. et al. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med. 371, 497–506 (2014).

    PubMed  PubMed Central  Google Scholar 

  212. Cho, M. Y. et al. First report of ovarian dysgerminoma in Cowden syndrome with germline PTEN mutation and PTEN-related 10q loss of tumor heterozygosity. Am. J. Surg. Pathol. 32, 1258–1264 (2008).

    PubMed  Google Scholar 

  213. Loveday, C. et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat. Genet. 44, 475–476; author reply 476 (2012).

    CAS  PubMed  Google Scholar 

  214. Birch, J. M. et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20, 4621–4628 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank K. Cimprich for communicating results prior to publication and B. Ejlertsen for helpful comments on the manuscript. The authors thank the Danish Cancer Society (C.S.S.), the Danish Medical Research Council (C.S.S.), the Neye Foundation (F.C.N.) and the Research Foundation for Health Research of the Capital Region of Denmark (F.C.N. and T.v.O.H.) for funding of their work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Claus Storgaard Sørensen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

Locus heterogeneity

A genetic term describing how variations in different genes cause the same disorder. The genes are not linked physically; examples are hereditary breast and ovarian cancer predisposition by BRCA1, BRCA2, partner and localizer of BRCA2 (PALB2) and TP53.

Homologous recombination repair

(HRR). A DNA repair pathway acting on DNA double-strand breaks that uses the undamaged sister chromatid as template for error-free repair. It is a multi-protein pathway involving a large number of factors, including BRCA1, BRCA2, partner and localizer of BRCA2 (PALB2) and RAD51 genes.

Mismatch repair

(MMR). A system for repairing erroneous insertion, deletion and misincorporation of bases arising during DNA replication. Mutations in MMR genes can result in microsatellite instability, which is implicated in most human cancers.

Interstrand DNA crosslink repair

Interstrand crosslinks (ICLs) occur through the covalent joining of opposite strands of the DNA helix. ICLs occur after reaction of DNA with natural products of metabolism or with chemotherapeutic reagents such as platinum compounds. ICL repair requires several DNA repair pathways including Fanconi anaemia and homologous recombination repair (HRR).

Fanconi anaemia

A bone marrow syndrome with enhanced predisposition to several cancers. It is a rare inherited disorder caused by mutations in several genes involved in the repair of DNA crosslinks, which includes the Fanconi anaemia factors FANCA and FANCE, BRCA1, BRCA2 and partner and localizer of BRCA2 (PALB2) genes.

Genotoxic stress

Cellular exposure to environmental and endogenous agents or conditions that can lead to genome alterations. If unrepaired as cells resume the cell division cycle, the altered genetic information leads to mutations, which may lead to cancer.

Cell cycle checkpoints

Signalling events during the cell cycle that prevent further progression.

Cyclin-dependent kinase

(CDK). Member of a class of kinases that associate with partner proteins termed cyclins. Specific CDKs are active at various phases of the cell cycle to promote cell cycle progression.

Platinum analogues

A class of chemotherapeutic agents, including cisplatin, oxaliplatin and carboplatin. Platinum compounds form intrastrand and interstrand crosslinks on DNA.

poly-(ADP-ribose) polymerase

(PARP). A class of enzymes involved in facilitating DNA repair.

Variant of unknown significance

(VUS). Variants in genes are classified according to their impact on the protein function. A variant with an unknown clinical function owing to lack of functional or clinical data is classified as a VUS.

Co-segregation

Genetic examination of several family members to clarify whether a specific variant is linked to a disease or not.

Mini-gene splicing analysis

A cell-based functional assay to establish whether a variant has an effect on splicing.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nielsen, F., van Overeem Hansen, T. & Sørensen, C. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer 16, 599–612 (2016). https://doi.org/10.1038/nrc.2016.72

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2016.72

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer