Breast Cancer Research and Treatment

, Volume 127, Issue 3, pp 671–679 | Cite as

International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

  • Ana Peixoto
  • Catarina Santos
  • Manuela Pinheiro
  • Pedro Pinto
  • Maria José Soares
  • Patrícia Rocha
  • Leonor Gusmão
  • António Amorim
  • Annemarie van der Hout
  • Anne-Marie Gerdes
  • Mads Thomassen
  • Torben A. Kruse
  • Dorthe Cruger
  • Lone Sunde
  • Yves-Jean Bignon
  • Nancy Uhrhammer
  • Lucie Cornil
  • Etienne Rouleau
  • Rosette Lidereau
  • Drakoulis Yannoukakos
  • Maroulio Pertesi
  • Steven Narod
  • Robert Royer
  • Maurício M. Costa
  • Conxi Lazaro
  • Lidia Feliubadaló
  • Begoña Graña
  • Ignacio Blanco
  • Miguel de la Hoya
  • Trinidad Caldés
  • Philippe Maillet
  • Gaelle Benais-Pont
  • Bruno Pardo
  • Yael Laitman
  • Eitan Friedman
  • Eladio A. Velasco
  • Mercedes Durán
  • Maria-Dolores Miramar
  • Ana Rodriguez Valle
  • María-Teresa Calvo
  • Ana Vega
  • Ana Blanco
  • Orland Diez
  • Sara Gutiérrez-Enríquez
  • Judith Balmaña
  • Teresa Ramon y Cajal
  • Carmen Alonso
  • Montserrat Baiget
  • William Foulkes
  • Marc Tischkowitz
  • Rachel Kyle
  • Nelly Sabbaghian
  • Patricia Ashton-Prolla
  • Ingrid P. Ewald
  • Thangarajan Rajkumar
  • Luisa Mota-Vieira
  • Giuseppe Giannini
  • Alberto Gulino
  • Maria I. Achatz
  • Dirce M. Carraro
  • Brigitte Bressac de Paillerets
  • Audrey Remenieras
  • Cindy Benson
  • Silvia Casadei
  • Mary-Claire King
  • Erik Teugels
  • Manuel R. Teixeira
Preclinical study

Abstract

The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement.

Keywords

c.156_157insAlu BRCA2 mutation Founder mutation Age estimation Hereditary breast/ovarian cancer 

Supplementary material

10549_2010_1036_MOESM1_ESM.doc (91 kb)
Supplementary fileDOC 91 kb
10549_2010_1036_MOESM2_ESM.tif (4.4 mb)
Supplementary Fig. 1Map of Portugal showing the known geographical origin of the families with the c.156_157insAlu BRCA2 germline mutation. The black circles indicate the origin of the 25 families detected in Portugal (present report and those reported in Peixoto et al. [6]), the open circle the origin of the family previously identified by Teugels et al. [4] in Belgium, and the triangles the origin of the families of the four individuals (two from each) subjected to predictive testing living in Rhode Island, USA, and in Villejuif, France, respectively. (TIF 4,506 kb)
10549_2010_1036_MOESM3_ESM.tif (6.9 mb)
Supplementary Fig. 2SNP marker haplotype spanning ~1.1Mb, encompassing the region between the D13S260 and D13S1695 microsatellite markers, in the 11 informative families. (TIF 7,026 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Ana Peixoto
    • 1
  • Catarina Santos
    • 1
  • Manuela Pinheiro
    • 1
  • Pedro Pinto
    • 1
  • Maria José Soares
    • 1
  • Patrícia Rocha
    • 1
  • Leonor Gusmão
    • 2
  • António Amorim
    • 2
    • 3
  • Annemarie van der Hout
    • 4
  • Anne-Marie Gerdes
    • 5
    • 6
  • Mads Thomassen
    • 5
  • Torben A. Kruse
    • 5
  • Dorthe Cruger
    • 7
  • Lone Sunde
    • 8
  • Yves-Jean Bignon
    • 9
  • Nancy Uhrhammer
    • 9
  • Lucie Cornil
    • 9
  • Etienne Rouleau
    • 10
  • Rosette Lidereau
    • 10
  • Drakoulis Yannoukakos
    • 11
  • Maroulio Pertesi
    • 11
  • Steven Narod
    • 12
  • Robert Royer
    • 12
  • Maurício M. Costa
    • 13
  • Conxi Lazaro
    • 14
  • Lidia Feliubadaló
    • 14
  • Begoña Graña
    • 14
  • Ignacio Blanco
    • 14
  • Miguel de la Hoya
    • 15
  • Trinidad Caldés
    • 15
  • Philippe Maillet
    • 16
  • Gaelle Benais-Pont
    • 16
  • Bruno Pardo
    • 16
  • Yael Laitman
    • 17
  • Eitan Friedman
    • 17
  • Eladio A. Velasco
    • 18
  • Mercedes Durán
    • 18
  • Maria-Dolores Miramar
    • 19
  • Ana Rodriguez Valle
    • 19
  • María-Teresa Calvo
    • 19
  • Ana Vega
    • 20
  • Ana Blanco
    • 20
  • Orland Diez
    • 21
    • 22
  • Sara Gutiérrez-Enríquez
    • 22
  • Judith Balmaña
    • 23
  • Teresa Ramon y Cajal
    • 24
  • Carmen Alonso
    • 24
  • Montserrat Baiget
    • 25
  • William Foulkes
    • 26
    • 27
    • 28
  • Marc Tischkowitz
    • 26
    • 28
  • Rachel Kyle
    • 26
    • 28
  • Nelly Sabbaghian
    • 26
    • 28
  • Patricia Ashton-Prolla
    • 29
    • 30
  • Ingrid P. Ewald
    • 29
    • 30
  • Thangarajan Rajkumar
    • 31
  • Luisa Mota-Vieira
    • 32
  • Giuseppe Giannini
    • 33
  • Alberto Gulino
    • 33
  • Maria I. Achatz
    • 34
  • Dirce M. Carraro
    • 35
  • Brigitte Bressac de Paillerets
    • 36
  • Audrey Remenieras
    • 36
  • Cindy Benson
    • 37
  • Silvia Casadei
    • 38
  • Mary-Claire King
    • 38
  • Erik Teugels
    • 39
  • Manuel R. Teixeira
    • 1
    • 40
  1. 1.Department of GeneticsPortuguese Oncology InstitutePortoPortugal
  2. 2.IPATIMUPPortoPortugal
  3. 3.Faculty of SciencesUniversity of PortoPortoPortugal
  4. 4.Department of GeneticsUniversity Medical Centre Groningen, University of GroningenGroningenThe Netherlands
  5. 5.Department of Clinical GeneticsOdense University HospitalOdenseDenmark
  6. 6.Department of Clinical GeneticsRigshospitalCopenhagenDenmark
  7. 7.Department of Clinical GeneticsVejle HospitalVejleDenmark
  8. 8.Department of Clinical GeneticsAalborg and Aarhus University HospitalsÅlborgDenmark
  9. 9.Deparment of OncogeneticsCentre Jean PerrinClermont-FerrandFrance
  10. 10.Laboratoire d’Oncogénétique—INSERM U735,Diagnostic Constitutionnel et SomatiqueInstitut Curie—Hôpital René HugueninSt. CloudFrance
  11. 11.Molecular Diagnostics Laboratory, IRRPNational Centre for Scientific Research “Demokritos”AthensGreece
  12. 12.Women’s College Research InstituteUniversity of TorontoTorontoCanada
  13. 13.Hospital Universitário Clementino Fraga Filho-UFRJRio de JaneiroBrazil
  14. 14.Laboratori de Recerca TranslacionalInstitut Català d’Oncologia, L’Hospitalet de LlobregatBarcelonaSpain
  15. 15.Laboratorio Oncología MolecularHospital Clínico San CarlosMadridSpain
  16. 16.Laboratory of Molecular OncologyUniversity Hospital of GenevaGenevaSwitzerland
  17. 17.Susanne-Levy Gertner Oncogenetics UnitThe Danek Gertner Institute of Genetics, Chaim Sheba Medical CenterTel-HashomerIsrael
  18. 18.Grupo de Genética del CáncerInstituto de Biología y Genética Molecular (UVa-CSIC)ValladolidSpain
  19. 19.Genetics UnitClinical Biochemistry ServiceZaragozaSpain
  20. 20.Fundación Pública Galega Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica—USCBER de enfermedades raras (CIBERER)GaliciaSpain
  21. 21.Oncogenetics LaboratoryUniversity Hospital Vall HebronBarcelonaSpain
  22. 22.Vall d’Hebron Institute of Oncology (VHIO)BarcelonaSpain
  23. 23.Department Medical OncologyUniversity Hospital Vall HebronBarcelonaSpain
  24. 24.Department of Medical OncologyHospital Sant PauBarcelonaSpain
  25. 25.Department of GeneticsHospital Sant PauBarcelonaSpain
  26. 26.McGill Program in Cancer Genetics, Departments of Human Genetics and OncologyMcGill UniversityMontrealCanada
  27. 27.The Research Institute, McGill University Health CentreMontrealCanada
  28. 28.Segal Cancer CentreLady Davis InstituteMontrealCanada
  29. 29.Department of Genetics and Molecular BiologyFederal University of Rio Grande do SulPorto AlegreBrazil
  30. 30.Department of Medical Genetics and Genomic Medicine LaboratoryHospital de Clinicas de Porto AlegrePorto AlegreBrazil
  31. 31.Cancer Institute (WIA)ChennaiIndia
  32. 32.Molecular Genetics and Pathology UnitHospital of Divino Espirito Santo of Ponta DelgadaSão Miguel IslandPortugal
  33. 33.Department of Experimental MedicineSapienza UniversityRomeItaly
  34. 34.Department of OncogeneticsHospital A.C.Camargo and National Institute of Science and Technology in OncogenomicsSão PauloBrazil
  35. 35.Laboratory of Genomics and Molecular BiologyHospital A.C.Camargo and National Institute of Science and Technology in OncogenomicsSão PauloBrazil
  36. 36.Department of GeneticsInstitut de Cancérologie Gustave RoussyVillejuifFrance
  37. 37.Genetic ClinicRhode Island HospitalProvidenceUSA
  38. 38.Departments of Medicine (Medical Genetics) and Genome SciencesUniversity of Washington School of MedicineSeattle, WashingtonUSA
  39. 39.Laboratory Molecular OncologyFree University of Brussels (VUB)BrusselsBelgium
  40. 40.Biomedical Sciences Institute (ICBAS)University of PortoPortoPortugal

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