Top

Published in:

01-01-2012 | Preclinical study

Cancer predisposing BARD1 mutations in breast–ovarian cancer families

Authors: Magdalena Ratajska, Ewelina Antoszewska, Anna Piskorz, Izabela Brozek, Åke Borg, Hanna Kusmierek, Wojciech Biernat, Janusz Limon

Published in: Breast Cancer Research and Treatment | Issue 1/2012

Abstract

The breast cancer susceptibility gene BARD1 (BRCA1-associated RING domain protein, MIM# 601593) acts with BRCA1 in DNA double-strand break (DSB) repair and also in apoptosis initiation. We screened 109 BRCA1/2 negative high-risk breast and/or ovarian cancer patients from North-Eastern Poland for BARD1 germline mutations using a combination of denaturing high-performance liquid chromatography and direct sequencing. We identified 16 different BARD1 sequence variants, five of which are novel. Three of them were suspected to be pathogenic, including a protein truncating nonsense mutation (c.1690C>T, p.Gln564X), a splice mutation (c.1315-2A>G) resulting in exon 5 skipping, and a silent change (c.1977A>G) which alters several exonic splicing enhancer motifs in exon 10 and results in a transcript lacking exons 2–9. Our findings suggest that BARD1 mutations may be regarded as cancer risk alleles and warrant further investigation to determine their actual contribution to non-BRCA1/2 breast and ovarian cancer families.

Antoniou AC, Pharoah PD, McMullan G, Day NE, Ponder BA, Easton D (2001) Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol 21:1–18. doi:10.1002/gepi.1014 PubMedCrossRef

Antoniou AC, Pharoah PD, McMullan G, Day NE, Stratton MR, Peto J, Ponder BJ, Easton DF (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76–83. doi:10.1038/sj.bjc.6600008 PubMedCrossRef

Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201. doi:10.1093/bioinformatics/bti770 PubMedCrossRef

Ars E, Kruyer H, Gaona A, Serra E, Lazaro C, Estivill X (1999) Prenatal diagnosis of sporadic neurofibromatosis type 1 (NF1) by RNA and DNA analysis of a splicing mutation. Prenat Diagn 19:739–742PubMedCrossRef

Ayi TC, Tsan JT, Hwang LY, Bowcock AM, Baer R (1998) Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein. Oncogene 17:2143–2148. doi:10.1038/sj.onc.1202123 PubMedCrossRef

Baralle D, Baralle M (2005) Splicing in action: assessing disease causing sequence changes. J Med Genet 42:737–748. doi:10.1136/jmg.2004.029538 PubMedCrossRef

Baralle M, Skoko N, Knezevich A, De Conti L, Motti D, Bhuvanagiri M, Baralle D, Buratti E, Baralle FE (2006) NF1 mRNA biogenesis: effect of the genomic milieu in splicing regulation of the NF1 exon 37 region. FEBS Lett 580:4449–4456. doi:10.1016/j.febslet.2006.07.018 PubMedCrossRef

Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM (2001) BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105:149–160PubMedCrossRef

Caputi M, Kendzior RJ Jr, Beemon KL (2002) A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer. Genes Dev 16:1754–1759. doi:10.1101/gad.997502 PubMedCrossRef

10.

Cartegni L, Krainer AR (2002) Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet 30:377–384. doi:10.1038/ng854 PubMedCrossRef

11.

Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571PubMedCrossRef

12.

De Brakeleer S, De Greve J, Loris R, Janin N, Lissens W, Sermijn E, Teugels E (2010) Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum Mutat 31:E1175–E1185. doi:10.1002/humu.21200 PubMedCrossRef

13.

den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12. doi:10.1002/(sici)1098-1004(200001)15:1<7:aid-humu4>3.0.co;2-n CrossRef

14.

Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67. doi:10.1093/nar/gkp215 PubMedCrossRef

15.

Easton DF (1999) How many more breast cancer predisposition genes are there? Breast Cancer Res 1:14–17PubMedCrossRef

16.

Erkko H, Xia B, Nikkila J, Schleutker J, Syrjakoski K, Mannermaa A, Kallioniemi A, Pylkas K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R (2007) A recurrent mutation in PALB2 in Finnish cancer families. Nature 446:316–319. doi:10.1038/nature05609 PubMedCrossRef

17.

Fackenthal JD, Cartegni L, Krainer AR, Olopade OI (2002) BRCA2 T2722R is a deleterious allele that causes exon skipping. Am J Hum Genet 71:625–631. doi:10.1086/342192 PubMedCrossRef

18.

Fox D 3rd, Le Trong I, Rajagopal P, Brzovic PS, Stenkamp RE, Klevit RE (2008) Crystal structure of the BARD1 ankyrin repeat domain and its functional consequences. J Biol Chem 283:21179–21186. doi:10.1074/jbc.M802333200 PubMedCrossRef

19.

Ghimenti C, Sensi E, Presciuttini S, Brunetti IM, Conte P, Bevilacqua G, Caligo MA (2002) Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosomes Cancer 33:235–242PubMedCrossRef

20.

Gorringe KL, Choong DY, Visvader JE, Lindeman GJ, Campbell IG (2008) BARD1 variants are not associated with breast cancer risk in Australian familial breast cancer. Breast Cancer Res Treat 111:505–509. doi:10.1007/s10549-007-9799-x PubMedCrossRef

21.

Hebsgaard SM, Korning PG, Tolstrup N, Engelbrecht J, Rouze P, Brunak S (1996) Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information. Nucleic Acids Res 24:3439–3452PubMedCrossRef

22.

Hedenfalk IA, Ringner M, Trent JM, Borg A (2002) Gene expression in inherited breast cancer. Adv Cancer Res 84:1–34PubMedCrossRef

23.

Heikkinen K, Karppinen SM, Soini Y, Makinen M, Winqvist R (2003) Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. J Med Genet 40:e131PubMedCrossRef

24.

Irminger-Finger I, Leung WC (2002) BRCA1-dependent and independent functions of BARD1. Int J Biochem Cell Biol 34:582–587PubMedCrossRef

25.

Ishitobi M, Miyoshi Y, Hasegawa S, Egawa C, Tamaki Y, Monden M, Noguchi S (2003) Mutational analysis of BARD1 in familial breast cancer patients in Japan. Cancer Lett 200:1–7PubMedCrossRef

26.

Jakubowska A, Cybulski C, Szymanska A, Huzarski T, Byrski T, Gronwald J, Debniak T, Gorski B, Kowalska E, Narod SA, Lubinski J (2008) BARD1 and breast cancer in Poland. Breast Cancer Res Treat 107:119–122. doi:10.1007/s10549-007-9537-4 PubMedCrossRef

27.

Jefford CE, Feki A, Harb J, Krause KH, Irminger-Finger I (2004) Nuclear-cytoplasmic translocation of BARD1 is linked to its apoptotic activity. Oncogene 23:3509–3520. doi:10.1038/sj.onc.1207427 PubMedCrossRef

28.

Karppinen SM, Heikkinen K, Rapakko K, Winqvist R (2004) Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. J Med Genet 41:e114. doi:10.1136/jmg.2004.020669 PubMedCrossRef

29.

Lewis AG, Flanagan J, Marsh A, Pupo GM, Mann G, Spurdle AB, Lindeman GJ, Visvader JE, Brown MA, Chenevix-Trench G (2005) Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer. Breast Cancer Res 7:R1005–R1016. doi:10.1186/bcr1336 PubMedCrossRef

30.

Li L, Cohen M, Wu J, Sow MH, Nikolic B, Bischof P, Irminger-Finger I (2007) Identification of BARD1 splice-isoforms involved in human trophoblast invasion. Int J Biochem Cell Biol 39:1659–1672. doi:10.1016/j.biocel.2007.04.018 PubMedCrossRef

31.

Li L, Ryser S, Dizin E, Pils D, Krainer M, Jefford CE, Bertoni F, Zeillinger R, Irminger-Finger I (2007) Oncogenic BARD1 isoforms expressed in gynecological cancers. Cancer Res 67:11876–11885. doi:10.1158/0008-5472.CAN-07-2370 PubMedCrossRef

32.

Liu HX, Cartegni L, Zhang MQ, Krainer AR (2001) A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat Genet 27:55–58. doi:10.1038/83762 PubMed

33.

Marquis ST, Rajan JV, Wynshaw-Boris A, Xu J, Yin GY, Abel KJ, Weber BL, Chodosh LA (1995) The developmental pattern of Brca1 expression implies a role in differentiation of the breast and other tissues. Nat Genet 11:17–26. doi:10.1038/ng0995-17 PubMedCrossRef

34.

McCarthy EE, Celebi JT, Baer R, Ludwig T (2003) Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Mol Cell Biol 23:5056–5063PubMedCrossRef

35.

Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59. doi:10.1038/ng879 PubMedCrossRef

36.

Meza JE, Brzovic PS, King MC, Klevit RE (1999) Mapping the functional domains of BRCA1. Interaction of the ring finger domains of BRCA1 and BARD1. J Biol Chem 274:5659–5665PubMedCrossRef

37.

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71PubMedCrossRef

38.

Mosor M, Ziolkowska-Suchanek I, Roznowski K, Baranowska M, Januszkiewicz-Lewandowska D, Nowak J (2010) RAD50 gene mutations are not likely a risk factor for breast cancer in Poland. Breast Cancer Res Treat 123:607–609. doi:10.1007/s10549-010-0992-y PubMedCrossRef

39.

Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11:863–874. doi:10.1101/gr.176601 PubMedCrossRef

40.

Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36. doi:10.1038/ng853 PubMedCrossRef

41.

Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358:2796–2803. doi:10.1056/NEJMsa0708739 PubMedCrossRef

42.

Ponder BA (2001) Cancer genetics. Nature 411:336–341. doi:10.1038/35077207 PubMedCrossRef

43.

Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Easton DF, Stratton MR (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39:165–167. doi:10.1038/ng1959 PubMedCrossRef

44.

Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900PubMedCrossRef

45.

Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comput Biol 4:311–323PubMedCrossRef

46.

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38:873–875. doi:10.1038/ng1837 PubMedCrossRef

47.

Rodriguez JA, Schuchner S, Au WW, Fabbro M, Henderson BR (2004) Nuclear-cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1. Oncogene 23:1809–1820. doi:10.1038/sj.onc.1207302 PubMedCrossRef

48.

Sabatier R, Adelaide J, Finetti P, Ferrari A, Huiart L, Sobol H, Chaffanet M, Birnbaum D, Bertucci F (2010) BARD1 homozygous deletion, a possible alternative to BRCA1 mutation in basal breast cancer. Genes Chromosomes Cancer 49:1143–1151. doi:10.1002/gcc.20822 PubMedCrossRef

49.

Sauer MK, Andrulis IL (2005) Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer. J Med Genet 42:633–638. doi:10.1136/jmg.2004.030049 PubMedCrossRef

50.

Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, Chagtai T, Jayatilake H, Ahmed M, Spanova K, North B, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38:1239–1241. doi:10.1038/ng1902 PubMedCrossRef

51.

Sedgwick SG, Smerdon SJ (1999) The ankyrin repeat: a diversity of interactions on a common structural framework. Trends Biochem Sci 24:311–316PubMedCrossRef

52.

Smith PJ, Zhang C, Wang J, Chew SL, Zhang MQ, Krainer AR (2006) An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers. Hum Mol Genet 15:2490–2508. doi:10.1093/hmg/ddl171 PubMedCrossRef

53.

Steffen J, Varon R, Mosor M, Maneva G, Maurer M, Stumm M, Nowakowska D, Rubach M, Kosakowska E, Ruka W, Nowecki Z, Rutkowski P, Demkow T, Sadowska M, Bidzinski M, Gawrychowski K, Sperling K (2004) Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. Int J Cancer 111:67–71. doi:10.1002/ijc.20239 PubMedCrossRef

54.

Steffen J, Nowakowska D, Niwinska A, Czapczak D, Kluska A, Piatkowska M, Wisniewska A, Paszko Z (2006) Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer 119:472–475. doi:10.1002/ijc.21853 PubMedCrossRef

55.

Swift M, Morrell D, Massey RB, Chase CL (1991) Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831–1836. doi:10.1056/nejm199112263252602 PubMedCrossRef

56.

Szybka M, Zawlik I, Kulczycka D, Golanska E, Jesien E, Kupnicka D, Stawski R, Piaskowski S, Bieniek E, Zakrzewska M, Kordek R, Liberski PP, Rieske P (2008) Elimination of wild-type P53 mRNA in glioblastomas showing heterozygous mutations of P53. Br J Cancer 98:1431–1433. doi:10.1038/sj.bjc.6604258 PubMedCrossRef

57.

Teraoka SN, Telatar M, Becker-Catania S, Liang T, Onengut S, Tolun A, Chessa L, Sanal O, Bernatowska E, Gatti RA, Concannon P (1999) Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet 64:1617–1631. doi:10.1086/302418 PubMedCrossRef

58.

Thai TH, Du F, Tsan JT, Jin Y, Phung A, Spillman MA, Massa HF, Muller CY, Ashfaq R, Mathis JM, Miller DS, Trask BJ, Baer R, Bowcock AM (1998) Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum Mol Genet 7:195–202PubMedCrossRef

59.

Vahteristo P, Syrjakoski K, Heikkinen T, Eerola H, Aittomaki K, von Smitten K, Holli K, Blomqvist C, Kallioniemi OP, Nevanlinna H (2006) BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition. Eur J Hum Genet 14:167–172. doi:10.1038/sj.ejhg.5201542 PubMedCrossRef

60.

Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11:103–105. doi:10.1016/j.ccr.2007.01.010 PubMedCrossRef

61.

Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, Yang MC, Hwang LY, Bowcock AM, Baer R (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14:430–440. doi:10.1038/ng1296-430 PubMedCrossRef

Title: Cancer predisposing BARD1 mutations in breast–ovarian cancer families
Authors: Magdalena Ratajska
Ewelina Antoszewska
Anna Piskorz
Izabela Brozek
Åke Borg
Hanna Kusmierek
Wojciech Biernat
Janusz Limon
Publication date: 01-01-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1403-8

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 STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

The vitamin D pathway and mammographic breast density among postmenopausal women

Breast cancer and spider telangiectasias at diagnosis and its relation to histopathology and prognosis: a population-based study

The BRCA2 c.9004G>A (E2003K) variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent

FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells

Phase II trial of a novel capecitabine dosing schedule in combination with lapatinib for the treatment of patients with HER2-positive metastatic breast cancer

Behavioral risk factors and their relationship to tumor characteristics in Hispanic and non-Hispanic white long-term breast cancer survivors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer