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

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 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 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 (1) , Rachel Kyle (1) , Nelly Sabbaghian (1) , Patricia Ashton-Prolla (29, 30) , Ingrid P. Ewald (1, 30) , Thangarajan Rajkumar (31) , Luisa Mota-Vieira (32) , Giuseppe Giannini (33) , Alberto Gulino (1) , Maria I. Achatz (34) , Dirce M. Carraro (35) , Brigitte Bressac Paillerets (36) , Audrey Remenieras (1) , Cindy Benson (37) , Silvia Casadei (38) , Mary-Claire King (1) , Erik Teugels (39) , Manuel R. Teixeira (1, 40)

1 Department of Genetics
2 IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto
3 Faculty of Sciences
4 Department of Genetics
5 Department of Clinical Genetics
6 Department of Clinical Genetics
7 Department of Clinical Genetics
8 Department of Clinical Genetics
9 Département d'Oncogénétique
10 Genetique Moleculaire des Cancers d'Origine Epitheliale
11 Molecular Diagnostics Laboratory, IRRP
12 Women's College Research Institute
13 HUCFF / UFRJ - Hospital Universitário Clementino Fraga Filho [Rio de Janeiro]
14 Laboratori de Recerca Translacional
15 Laboratorio Oncología Molecular
16 Laboratory of Molecular Oncology
17 Susanne-Levy Gertner Oncogenetics Unit
18 Grupo de Genética del Cáncer
19 Genetics Unit
20 Fundación Pública Galega Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica--USC
21 Oncogenetics Laboratory
22 VHIO - Vall d'Hebron Institute of Oncology [Barcelone]
23 Department Medical Oncology
24 Department of Medical Oncology
25 Department of Genetics
26 Department of Human Genetics [Montréal]
27 MUHC - McGill University Health Center [Montreal]
28 Segal Cancer Centre
29 Department of Genetics and Molecular Biology
30 Department of Medical Genetics and Genomic Medicine Laboratory
31 Cancer Institute (WIA)
32 Molecular Genetics and Pathology Unit
33 Department of Experimental Medicine
34 Department of Oncogenetics
35 Laboratory of Genomics and Molecular Biology
36 Génétique (Biologie pathologie)
37 Genetic Clinic
38 Departments of Medicine (Medical Genetics) and Genome Sciences
39 Laboratory Molecular Oncology
40 Biomedical Sciences Institute (ICBAS)

The c.156_157insAlu 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 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 full length RNA and the transcript lacking exon 3 in c.156_157insAlu mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other and pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement.

Mots clés: c.156_157insAlu mutation; Founder mutation; Age estimation; Hereditary breast/ovarian cancer

Ana Peixoto, Catarina Santos, Manuela Pinheiro, Pedro Pinto, Maria José Soares, et al.. International distribution and age estimation of the Portuguese c.156_157insAlu founder mutation. Breast Cancer Research and Treatment, 2010, 127 (3), pp.671-679. ⟨10.1007/s10549-010-1036-3⟩. ⟨hal-00615365⟩