Top

Published in:

01-01-2019 | Review

BRCA mutations: is everything said?

Authors: Eduardo López-Urrutia, Victor Salazar-Rojas, Luis Brito-Elías, Misael Coca-González, Jonathan Silva-García, David Sánchez-Marín, Alma D. Campos-Parra, Carlos Pérez-Plasencia

Published in: Breast Cancer Research and Treatment | Issue 1/2019

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.

Available only for authorised users

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

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 CrossRefPubMed

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRef

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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.

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 CrossRefPubMed

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 57:828–831PubMed

15.

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

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 CrossRefPubMedPubMedCentral

17.

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

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

28.

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

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 88:519–524CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

39.

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

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

Title: BRCA mutations: is everything said?
Authors: Eduardo López-Urrutia
Victor Salazar-Rojas
Luis Brito-Elías
Misael Coca-González
Jonathan Silva-García
David Sánchez-Marín
Alma D. Campos-Parra
Carlos Pérez-Plasencia
Publication date: 01-01-2019
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4986-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Aim

Results

Please log in to get access to this content

Other articles of this Issue 1/2019

COOLHAIR: a prospective randomized trial to investigate the efficacy and tolerability of scalp cooling in patients undergoing (neo)adjuvant chemotherapy for early breast cancer

Correction to: Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung

The prognostic value of tumour–stroma ratio in primary breast cancer with special attention to triple-negative tumours: a review

Dietary intervention among breast cancer survivors increased adherence to a Mediterranean-style, anti-inflammatory dietary pattern: the Rx for Better Breast Health Randomized Controlled Trial

The association of socioeconomic status with receipt of neoadjuvant chemotherapy

Regular exercise might be associated with higher skeletal muscle volume, favorable prognostic factor in breast cancer patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer