Abstract
The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340–1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct ∼6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140–300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.
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Acknowledgements
We wish to thank the families for participating in this study by donating blood samples and Dr Mike Stratton at the Institute of Cancer Research, Sutton, Surrey, UK, for kindly providing information for the SLS markers used and Dr Hannaleena Eerola and Ms Minna Merikivi, R.N. at the Department of Oncology, Helsinki University Hospital, for their kind help. Professor Jonas Hallgrimsson and the staff at the Department of Pathology, Iceland is gratefully acknowledged for access to tissue samples, Anna G Hafsteinsdottir, Oddny Vilhjalmsdottir at the Genetic Committee, University of Iceland for help with the pedigree data, the Red Cross in Tampere, Finland, and the Blood Bank of Iceland for providing the blood samples for allele frequency estimations. We also warmly thank Elizabeth Gillanders and Diana Freas-Lutz at NHGRI for technical advice and support, Ella Kristin Geirsdottir, Gudrun Johannesdottir and Omar Kristinsson at Department of Pathology, Iceland, for technical assistance and Sigrun Kristjansdottir and Kristrun Olafsdottir at the Department of Pathology, Iceland , for the help with tissue processing. This work was supported by the Nordic Cancer Union, Finnish Cancer Society, the Sigrid Juselius Foundation and the Clinical Research Fund of Helsinki University Central Hospital.
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Barkardottir, R., Sarantaus, L., Arason, A. et al. Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families. Eur J Hum Genet 9, 773–779 (2001). https://doi.org/10.1038/sj.ejhg.5200717
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DOI: https://doi.org/10.1038/sj.ejhg.5200717
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