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BMC Medical Genetics

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Open Access 01-12-2011 | Research article

The occurrence of germline BRCA1 and BRCA2sequence alterations in Slovenian population

Authors: Vida Stegel, Mateja Krajc, Janez Žgajnar, Erik Teugels, Jacques De Grève, Marko Hočevar, Srdjan Novaković

Published in: BMC Medical Genetics | Issue 1/2011

Abstract

Background

The BRCA1 and BRCA2 mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer.

Methods

The BRCA1 and BRCA2 genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing.

Results

Eighteen different mutations were found in BRCA1 and 13 in BRCA2 gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for BRCA1 and 8% for BRCA2. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for BRCA1 and 13% for BRCA2. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for BRCA1 and 8% for BRCA2. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for BRCA2 and 0% for BRCA1.

Conclusion

Among the mutations detected in Slovenian population, 5 mutations in BRCA1 and 4 mutations in BRCA2 have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in BRCA1 gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in BRCA2 gene (detected in 69% of BRCA1 and BRCA2 positive families).

Primic Žakelj M, Bračko M, Hočevar M, Krajc M, Pompe Kirn V, Strojan P, Zadnjik V, Zakotnik B, Žagar T, eds: Cancer in Slovenia 2007. 2010, Ljubljana, Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia

Claus EB, Risch N, Thompson WD: Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet. 1991, 48 (2): 232-42.PubMedPubMedCentral

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhasen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994, 266 (5182): 66-71. 10.1126/science.7545954.CrossRefPubMed

Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G: Identification of the breast cancer susceptibilitygene BRCA2. Nature. 1995, 378 (6559): 789-92. 10.1038/378789a0.CrossRefPubMed

Smith SA, Easton DF, Evans DG, Ponder BA: Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nat Genet. 1992, 2 (2): 128-31. 10.1038/ng1092-128.CrossRefPubMed

Collins N, McManus R, Wooster R, Mangion J, Seal S, Lakhani SR, Ormiston W, Daly PA, Ford D, Easton DF, Stratton MR: Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13. Oncogene. 1995, 10 (8): 1673-5.PubMed

Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE: Risks of cancer in BRCA1-mutation carriers. Lancet. 1994, 343 (8899): 692-5. 10.1016/S0140-6736(94)91578-4. Breast Cancer Linkage ConsortiumCrossRefPubMed

Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am J Hum Genet. 1995, 56 (1): 265-71. Breast Cancer Linkage ConsortiumPubMedPubMedCentral

Couch FJ, Farid LM, DeShano ML, Tavtigian SV, Calzone K, Campeau L, Peng Y, Bogden B, Chen Q, Neuhausen S, Shattuck-Eidens D, Godwin AK, Daly M, Radford DM, Sedlacek S, Rommens J, Simard J, Garber J, Merajver S, Weber BL: BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996, 13 (1): 123-5. 10.1038/ng0596-123.CrossRefPubMed

10.

Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjäkoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003, 72 (5): 1117-30. 10.1086/375033.CrossRefPubMedPubMedCentral

11.

King MC, Marks JH, Mandell JB, New York Breast Cancer Study Group: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003, 302 (5645): 643-6. 10.1126/science.1088759.CrossRefPubMed

12.

Narod SA, Ford D, Devilee P, Barkardottir RB, Lynch HT, Smith SA, Ponder BA, Weber BL, Garber JE, Birch JM, Cornelis RS, Kelsell DP, Spurr NK, Smyth E, Haites N, Sobol H, Bignon YJ, Chang-Claude J, Hamann U, Lindblom A, Borg AM, Steven Piver MS, Gallion HH, Struewing JP, Whittemore A, Tonin P, Goldgar DE, Easton DF: An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am J Hum Genet. 1995, 56 (1): 254-64. Breast Cancer Linkage ConsortiumPubMedPubMedCentral

13.

Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, Peterson LE, Schildkraut JM, Isaacs C, Peshkin BN, Corio C, Leondaridis L, Tomlinson G, Dutson D, Kerber R, Amos CI, Strong LC, Berry DA, Euhus DM, Parmigiani G: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006, 24 (6): 863-71. 10.1200/JCO.2005.03.6772.CrossRefPubMedPubMedCentral

14.

Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998, 62 (3): 676-89. 10.1086/301749. The Breast Cancer Linkage ConsortiumCrossRefPubMedPubMedCentral

15.

Meindl A, German Consortium for Hereditary Breast and Ovarian Cancer: Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002, 97 (4): 472-80. 10.1002/ijc.1626.CrossRefPubMed

16.

Machackova E, Foretova L, Lukesova M, Vasickova P, Navratilova M, Coene I, Pavlu H, Kosinova V, Kuklova J, Claes K: Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008, 20 (8): 140-10.1186/1471-2407-8-140.CrossRef

17.

Verhoog LC, van den Ouweland AM, Berns E, van Veghel-Plandsoen MM, van Staveren IL, Wagner A, Bartels CC, Tilanus-Linthorst MM, Devilee P, Seynaeve C, Halley DJ, Niermeijer MF, Klijn JG, Meijers-Heijboer H: Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. Eur J Cancer. 2001, 37 (16): 2082-90. 10.1016/S0959-8049(01)00244-1.CrossRefPubMed

18.

Stoppa-Lyonnet D, Laurent-Puig P, Essioux L, Pagès S, Ithier G, Ligot L, Fourquet A, Salmon RJ, Clough KB, Pouillart P, Bonaïti-Pellié C, Thomas G: BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Am J Hum Genet. 1997, 60 (5): 1021-30. Institut Curie Breast Cancer GroupPubMedPubMedCentral

19.

Håkansson S, Johannsson O, Johansson U, Sellberg G, Loman N, Gerdes AM, Holmberg E, Dahl N, Pandis N, Kristoffersson U, Olsson H, Borg A: Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997, 60 (5): 1068-78.PubMedPubMedCentral

20.

Vehmanen P, Friedman LS, Eerola H, McClure M, Ward B, Sarantaus L, Kainu T, Syrjäkoski K, Pyrhönen S, Kallioniemi OP, Muhonen T, Luce M, Frank TS, Nevanlinna H: Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. Hum Mol Genet. 1997, 6 (13): 2309-15. 10.1093/hmg/6.13.2309.CrossRefPubMed

21.

Goelen G, Teugels E, Bonduelle M, Neyns B, De Grève J: High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects. J Med Genet. 1999, 36 (4): 304-8.PubMedPubMedCentral

22.

De Grève J, Sermijn E, De Brakeleer S, Ren Z, Teugels E: Hereditary breast cancer: from bench to bedside. Curr Opin Oncol. 2008, 20 (6): 605-13.CrossRefPubMed

23.

de la Hoya M, Osorio A, Godino J, Sulleiro S, Tosar A, Perez-Segura P, Fernandez C, Rodríguez R, Díaz-Rubio E, Benítez J, Devilee P, Caldés T: Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002, 97 (4): 466-71. 10.1002/ijc.1627.CrossRefPubMed

24.

Wagner TM, Möslinger RA, Muhr D, Langbauer G, Hirtenlehner K, Concin H, Doeller W, Haid A, Lang AH, Mayer P, Ropp E, Kubista E, Amirimani B, Helbich T, Becherer A, Scheiner O, Breiteneder H, Borg A, Devilee P, Oefner P, Zielinski C: BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics. Int J Cancer. 1998, 77 (3): 354-60. 10.1002/(SICI)1097-0215(19980729)77:3<354::AID-IJC8>3.0.CO;2-N.CrossRefPubMed

25.

Giannini G, Capalbo C, Ristori E, Ricevuto E, Sidoni T, Buffone A, Cortesi E, Marchetti P, Scambia G, Tomao S, Rinaldi C, Zani M, Ferraro S, Frati L, Screpanti I, Gulino A: 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. 2006, 100 (1): 83-91. 10.1007/s10549-006-9225-9.CrossRefPubMed

26.

Capalbo C, Ricevuto E, Vestri A, Ristori E, Sidoni T, Buffone O, Adamo B, Cortesi E, Marchetti P, Scambia G, Tomao S, Rinaldi C, Zani M, Ferraro S, Frati L, Screpanti I, Gulino A, Giannini G: 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. 2006, 17 (Suppl 7): 34-40. vii

27.

Ottini L, Rizzolo P, Zanna I, Falchetti M, Masala G, Ceccarelli K, Vezzosi V, Gulino A, Giannini G, Bianchi S, Sera F, Palli D: BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in central Italy. Breast Cancer Res Treat. 2009, 116 (3): 577-86. 10.1007/s10549-008-0194-z.CrossRefPubMed

28.

Stuppia L, Di Fulvio P, Aceto G, Pintor S, Veschi S, Gatta V, Colosimo A, Cianchetti E, Cama A, Mariani-Costantini R, Battista P, Palka G: BRCA1 and BRCA2 mutations in breast/ovarian cancer patients from central Italy. Hum Mutat. 2003, 22 (2): 178-9. 10.1002/humu.9164.CrossRefPubMed

29.

Ottini L, D'Amico C, Noviello C, Lauro S, Lalle M, Fornarini G, Colantuoni OA, Pizzi C, Cortesi E, Carlini S, Guadagni F, Bianco AR, Frati L, Contegiacomo A, Mariani-Costantini R: BRCA1 and BRCA2 mutations in central and southern Italian patients. Breast Cancer Res. 2000, 2 (4): 307-10. 10.1186/bcr72.CrossRefPubMedPubMedCentral

30.

Novaković S, Stegel V: Rapid detection of most frequent Slovenian germ-line mutations in BRCA1 gene using real-time PCR and melting curve analysis. Radiol Oncol. 2005, 39: 147-152.

31.

Krajc M, De Grève J, Goelen G, Teugels E: BRCA2 founder mutation in Slovenian breast cancer families. Eur J Hum Genet. 2002, 10 (12): 879-82. 10.1038/sj.ejhg.5200886.CrossRefPubMed

32.

Human Genome Variation Society internet web site: [http://www.hgvs.org/mutnomen/]

33.

Breast Cancer Information Core internet web site: [http://research.nhgri.nih.gov/bic/]

34.

Ramus SJ, Harrington PA, Pye C, DiCioccio RA, Cox MJ, Garlinghouse-Jones K, Oakley-Girvan I, Jacobs IJ, Hardy RM, Whittemore AS, Ponder BA, Piver MS, Pharoah PD, Gayther SA: Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutat. 2007, 28 (12): 1207-15. 10.1002/humu.20599.CrossRefPubMed

35.

Ramus SJ, Gayther SA: The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol. 2009, 3 (2): 138-50. 10.1016/j.molonc.2009.02.001.CrossRefPubMed

36.

Song H, Ramus SJ, Tyrer J, Bolton KL, Gentry-Maharaj A, Wozniak E, Anton-Culver H, Chang-Claude J, Cramer DW, DiCioccio R, Dörk T, Goode EL, Goodman MT, Schildkraut JM, Sellers T, Baglietto L, Beckmann MW, Beesley J, Blaakaer J, Carney ME, Chanock S, Chen Z, Cunningham JM, Dicks E, Doherty JA, Dürst M, Ekici AB, Fenstermacher D, Fridley BL, Giles, et al: A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet. 2009, 41 (9): 996-1000. 10.1038/ng.424.CrossRefPubMedPubMedCentral

37.

De Brakeleer S, De Grève J, Loris R, Janin N, Lissens W, Sermijn E, Teugels E: Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum Mutat. 2010, 31 (3): E1175-85. 10.1002/humu.21200.CrossRefPubMed

38.

Besic N, Cernivc B, de Grève J, Lokar K, Krajc M, Novakovic S, Zgajnar J, Teugels E: BRCA2 gene mutations in Slovenian male breast cancer patients. Genet Test. 2008, 12 (2): 203-9. 10.1089/gte.2007.0071.CrossRefPubMed

39.

Krajc M, Teugels E, Zgajnar J, Goelen G, Besic N, Novakovic S, Hocevar M, De Grève J: Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families. BMC Med Genet. 2008, 10 (9): 83-90. 10.1186/1471-2350-9-83.CrossRef

40.

Santarosa M, Dolcetti R, Magri MD, Crivellari D, Tibiletti MG, Gallo A, Tumolo S, Della Puppa L, Furlan D, Boiocchi M, Viel A: BRCA1 and BRCA2 genes: role in hereditary breast and ovarian cancer in Italy. Int J Cancer. 1999, 83 (1): 5-9. 10.1002/(SICI)1097-0215(19990924)83:1<5::AID-IJC2>3.0.CO;2-U.CrossRefPubMed

41.

Miolo G, Puppa LD, Santarosa M, De Giacomi C, Veronesi A, Bidoli E, Tibiletti MG, Viel A, Dolcetti R: Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in north-east of Italy. BMC Cancer. 2006, 9: 6:156-

42.

Latif A, McBurney HJ, Roberts SA, Lalloo F, Howell A, Evans DG, Newman WG: Breast cancer susceptibility variants alter risk in familial ovarian cancer. Fam Cancer. 2010, Published online First

43.

Loizidou MA, Cariolou MA, Neuhausen SL, Newbold RF, Bashiardes E, Marcou Y, Michael T, Daniel M, Kakouri E, Papadopoulos P, Malas S, Hadjisavvas A, Kyriacou K: Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population. Breast Cancer Res Treat. 2010, 121 (1): 147-56. 10.1007/s10549-009-0518-7.CrossRefPubMed

44.

Palanca Suela S, Esteban Cardeñosa E, Barragán González E, Oltra Soler S, de Juan Jiménez I, Chirivella González I, Segura Huerta A, Guillén Ponce C, Martínez de Dueñas E, Bolufer Gilabert P: Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast/ovarian cancer family. Breast Cancer Res Treat. 2008, 112 (1): 63-7. 10.1007/s10549-007-9839-6.CrossRefPubMed

45.

Vasickova P, Machackova E, Lukesova M, Damborsky J, Horky O, Pavlu H, Kuklova J, Kosinova V, Navratilova M, Foretova L: High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic. BMC Med Genet. 2007, 11: 8:32-

46.

Hartmann C, John AL, Klaes R, Hofmann W, Bielen R, Koehler R, Janssen B, Bartram CR, Arnold N, Zschocke J: Large BRCA1 gene deletions are found in 3% of German high-risk breast cancer families. Hum Mutat. 2004, 24 (6): 534-10.1002/humu.9291.CrossRefPubMed

47.

Konecny M, Vizvaryova M, Weismanova E, Ilencikova D, Mlkva I, Weismann P, Machackova G, Kausitz J: The spectrum and incidence of BRCA1 pathogenic mutations in Slovak breast/ovarian cancer families. Neoplasma. 2007, 54 (2): 137-42.PubMed

48.

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA: Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst. 2006, 98 (23): 1694-706. 10.1093/jnci/djj465.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/12/9/prepub

Title: The occurrence of germline BRCA1 and BRCA2sequence alterations in Slovenian population
Authors: Vida Stegel
Mateja Krajc
Janez Žgajnar
Erik Teugels
Jacques De Grève
Marko Hočevar
Srdjan Novaković
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2011
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-12-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The occurrence of germline BRCA1 and BRCA2sequence alterations in Slovenian population

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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