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.
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Acknowledgments
This study was supported by Ministério da Saúde (Project Nº 15/2007) and Liga Portuguesa Contra o Cancro. IPATIMUP was funded by Fundação para a Ciência e Tecnologia, through POCI (Programa Operacional Ciência e Inovação 2010). MT and WDF are supported by the Susan G. Komen Foundation for the Cure, the Jewish General Hospital Weekend to End Breast Cancer and the Fonds de la Recherche en Santé du Québec. EAV and MD are supported by grants PI061102 (Ministerio de Ciencia e Innovación) and 200820I135 (CSIC). AV and AB thank María J. Magdalena for her excellent technical support at the Fundación Pública Galega de Medicina Xenómica. PAP and IPE were supported by CNPq, CAPES, Fundação de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre, and Rede Nacional de Câncer Familial, Brazil. The authors declare that they have no conflict of interest.
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Supplementary Fig. 1
Map 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)
Supplementary Fig. 2
SNP 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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Peixoto, A., Santos, C., Pinheiro, M. et al. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation. Breast Cancer Res Treat 127, 671–679 (2011). https://doi.org/10.1007/s10549-010-1036-3
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DOI: https://doi.org/10.1007/s10549-010-1036-3