BRCA mutations: is everything said?

Abstract

Background

Mutations in the BRCA1 and BRCA2 genes constitute a risk factor for breast cancer development. BRCA mutation research has been an active field since the discovery of the genes, and new mutations in both genes are constantly described and classified according to several systems.

Aim

We intend to provide an overview of the current state of BRCA1 and BRCA2 mutation description and classification. We wanted to know whether there was a trend towards a more frequently described mutation type and what the proportion of pathogenic mutations was.

Results

We found that, although new mutations are described each year as reflected in current database records, very few of them are reported in papers. Classification systems are highly heterogeneous and a consensus among them is still under development. Regarding their function, a large number of mutations are yet to be analyzed, a very complex task, due to the great number of possible variations and their diverse effect in the BRCA gene functions. After individual analysis, many variants of unknown significance turn out to be pathogenic, and many can disrupt interactions with other proteins involved in mechanisms such as DNA damage repair pathways. Recent data suggest that looking for mutation patterns or combinations would shed a wider light on BRCA-derived cancer susceptibility in the upcoming years.

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

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    BIC Consortium (1995) Breast cancer information core. https://research.nhgri.nih.govprojectsbic

  2. 2.

    Landrum MJ, Lee JM, Benson M et al (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44:D862–D868. https://doi.org/10.1093/nar/gkv1222

    Article  CAS  Google Scholar 

  3. 3.

    Dunnen den J, Antonarakis E (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121–124. https://doi.org/10.1007/s004390100505

    Article  CAS  Google Scholar 

  4. 4.

    Antonarakis SE (1998) Recommendations for a nomenclature system for human gene mutations. Hum Mutat 11:1–3. https://doi.org/10.1002/(SICI)1098-1004(1998)11:1%3C1::AID-HUMU1%3E3.0.CO;2-O

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Capalbo C, Ricevuto E, Vestri A et al (2006) BRCA1 and BRCA2 genetic testing in Italian breast and/or ovarian cancer families: mutation spectrum and prevalence and analysis of mutation prediction models. Ann Oncol 17:vii34–vii40. https://doi.org/10.1093/annonc/mdl947

    Article  PubMed  Google Scholar 

  6. 6.

    Giannini G, Capalbo C, Ristori E et al (2006) Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families. Breast Cancer Res Treat 100:83–91. https://doi.org/10.1007/s10549-006-9225-9

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Eccles DM, Mitchell G, Monteiro ANA et al (2015) BRCA1 and BRCA2 genetic testing—pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol 26:2057–2065. https://doi.org/10.1093/annonc/mdv278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Lincoln SE, Yang S, Cline MS et al (2017) Consistency of BRCA1 and BRCA2 variant classifications among clinical diagnostic laboratories. JCO Precis Oncol 1:721–722. https://doi.org/10.1038/gim.2016.196

    CAS  Article  Google Scholar 

  9. 9.

    Chenevix-Trench G, Milne RL, Antoniou AC et al (2007) An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9:104. https://doi.org/10.1186/bcr1670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Spurdle AB, Healey S, Devereau A et al (2012) 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. https://doi.org/10.1002/humu.21628

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Forbes S, Clements J, Dawson E et al (2006) COSMIC 2005. Br J Cancer 94:318–322. https://doi.org/10.1038/sj.bjc.6602928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    2006 Human Variome Project, Appelbe W, Auerbach AD et al (2007) Recommendations of the 2006 human variome project meeting. In: Nat. Genet. pp 433–436

  13. 13.

    Couch FJ, Weber BL (1996) Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Hum Mutat 8:8–18. https://doi.org/10.1002/humu.1380080102

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Puget N, Torchard D, Serova-Sinilnikova OM et al (1997) A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res 57:828–831

    CAS  PubMed  Google Scholar 

  15. 15.

    Mazoyer S (2005) Genomic rearrangements in theBRCA1 andBRCA2 genes. Hum Mutat 25:415–422. https://doi.org/10.1002/humu.20169

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Borg A, Haile RW, Malone KE et al (2010) Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat 31:E1200–E1240. https://doi.org/10.1002/humu.21202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Szabo CI, King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60:1013–1020

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Fackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7:937–948. https://doi.org/10.1038/nrc2054

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Ewald IP, Ribeiro PLI, Palmero EI et al (2009) Genomic rearrangements in BRCA1 and BRCA2: a literature review. Genet Mol Biol 32:437–446. https://doi.org/10.1590/S1415-47572009005000049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Karami F, Mehdipour P (2013) A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. Biomed Res Int 2013:928562. https://doi.org/10.1155/2013/928562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Rebbeck TR, Friebel TM, Friedman E et al (2018) Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593–620. https://doi.org/10.1002/humu.23406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Maillet P, Chappuis PO, Khoshbeen-Boudal M et al (2006) Twenty-three novel BRCA1 and BRCA2 sequence variations identified in a cohort of Swiss breast and ovarian cancer families. Cancer Genet Cytogenet 169:62–68. https://doi.org/10.1016/j.cancergencyto.2006.03.010

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Lee MS, Green R, Marsillac SM et al (2010) Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res 70:4880–4890. https://doi.org/10.1158/0008-5472.CAN-09-4563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Steffensen AY, Dandanell M, Jønson L et al (2014) Functional characterization of BRCA1 gene variants by mini-gene splicing assay. Eur J Hum Genet 22:1362–1368. https://doi.org/10.1038/ejhg.2014.40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Easton DF, Deffenbaugh AM, Pruss D et al (2007) A systematic genetic assessment of 1433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 81:873–883. https://doi.org/10.1086/521032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Vallée MP, Francy TC, Judkins MK et al (2012) Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum Mutat 33:22–28. https://doi.org/10.1002/humu.21629

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Kurz EU, Lees-Miller SP (2004) DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair 3:889–900. https://doi.org/10.1016/j.dnarep.2004.03.029

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Christou C, Kyriacou K (2013) BRCA1 and its network of interacting partners. Biology 2:40–63. https://doi.org/10.3390/biology2010040

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Takaoka M, Miki Y (2017) BRCA1 gene: function and deficiency. Int J Clin Oncol 23:36–44. https://doi.org/10.1007/s10147-017-1182-2

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Knijnenburg TA, Wang L, Zimmermann MT et al (2018) Genomic and molecular landscape of DNA Damage repair deficiency across the cancer genome atlas. Cell Rep 23:239–254.e6. https://doi.org/10.1016/j.celrep.2018.03.076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Frazer KA, Murray SS, Schork NJ, Topol EJ (2009) Human genetic variation and its contribution to complex traits. Nat Rev Genet 10:241–251. https://doi.org/10.1038/nrg2554

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Di Giacomo D, Gaildrat P, Abuli A et al (2013) Functional Analysis of a Large set of BRCA2exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements. Hum Mutat 34:1547–1557. https://doi.org/10.1002/humu.22428

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Soukarieh O, Gaildrat P, Hamieh M et al (2016) Exonic splicing mutations are more prevalent than currently estimated and can be predicted by using in silico tools. PLoS Genet 12:e1005756–e1005726. https://doi.org/10.1371/journal.pgen.1005756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wang Y, Bernhardy AJ, Cruz C et al (2016) The BRCA1-∆11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin. Cancer Res 76:2778–2790. https://doi.org/10.1158/0008-5472.CAN-16-0186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Bachelier R, Dalla Venezia N, Mazoyer S et al (2000) Differential expression and subcellular localization of murine BRCA1 and BRCA1-delta 11 isoforms in murine and human cell lines. Int J Cancer 88:519–524

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Wang X, Wang R-H, Li W et al (2004) Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. J Biol Chem 279:29606–29614. https://doi.org/10.1074/jbc.M312279200

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Elstrodt F, Hollestelle A, Nagel JHA et al (2006) BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. Cancer Res 66:41–45. https://doi.org/10.1158/0008-5472.CAN-05-2853

    Article  CAS  Google Scholar 

  38. 38.

    Doss CGP, Nagasundaram N (2014) An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex. Cell Biochem Biophys 70:939–956. https://doi.org/10.1007/s12013-014-0002-9

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Kean S (2014) Breast cancer. The “other” breast cancer genes. Science 343:1457–1459. https://doi.org/10.1126/science.343.6178.1457

    Article  PubMed  Google Scholar 

  40. 40.

    Antoniou AC, Casadei S, Heikkinen T et al (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497–506. https://doi.org/10.1056/NEJMoa1400382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Song H, Dicks E, Ramus SJ et al (2015) Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 33:2901–2907. https://doi.org/10.1200/JCO.2015.61.2408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Sánchez-Bermúdez AI, Sarabia-Meseguer MD, García-Aliaga Á et al (2018) Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet 61:355–361. https://doi.org/10.1016/j.ejmg.2018.01.015

    Article  PubMed  Google Scholar 

Download references

Funding

This study was funded by DGAPA-PAPIIT, Universidad Nacional Autónoma de México with Grant Number IA201216, awarded to E.L-U. and grant number IN207216, awarded to C.P-P.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Eduardo López-Urrutia or Carlos Pérez-Plasencia.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

López-Urrutia, E., Salazar-Rojas, V., Brito-Elías, L. et al. BRCA mutations: is everything said?. Breast Cancer Res Treat 173, 49–54 (2019). https://doi.org/10.1007/s10549-018-4986-5

Download citation

Keywords

  • Breast cancer risk
  • BRCA1
  • BRCA2
  • Mutation
  • Complex traits