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Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families

Arason, Adalgeir; Gunnarsson, Haukur; Johannesdottir, Gudrun; Jonasson, Kristjan; Bendahl, Pär-Ola LU ; Gillanders, Elizabeth M.; Agnarsson, Bjarni A.; Jönsson, Göran B LU ; Pylkas, Katri and Mustonen, Aki, et al. (2010) In Breast Cancer Research 12(4).
Abstract
Introduction: A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. Methods:... (More)
Introduction: A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. Methods: GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene. Results: The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer. Conclusions: Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction. (Less)
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Breast Cancer Research
volume
12
issue
4
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BioMed Central
external identifiers
  • wos:000285504100006
  • scopus:78650859181
ISSN
1465-5411
DOI
10.1186/bcr2608
language
English
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623c9c0a-51cf-4f37-98ee-0d55f90a431d (old id 1831215)
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2011-03-02 11:22:34
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2018-05-29 09:35:39
@article{623c9c0a-51cf-4f37-98ee-0d55f90a431d,
  abstract     = {Introduction: A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. Methods: GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene. Results: The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer. Conclusions: Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.},
  author       = {Arason, Adalgeir and Gunnarsson, Haukur and Johannesdottir, Gudrun and Jonasson, Kristjan and Bendahl, Pär-Ola and Gillanders, Elizabeth M. and Agnarsson, Bjarni A. and Jönsson, Göran B and Pylkas, Katri and Mustonen, Aki and Heikkinen, Tuomas and Aittomaki, Kristiina and Blomqvist, Carl and Melin, Beatrice and Johannsson, Oskar T. H. and Moller, Pal and Winqvist, Robert and Nevanlinna, Heli and Borg, Åke and Barkardottir, Rosa B.},
  issn         = {1465-5411},
  language     = {eng},
  number       = {4},
  publisher    = {BioMed Central},
  series       = {Breast Cancer Research},
  title        = {Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families},
  url          = {http://dx.doi.org/10.1186/bcr2608},
  volume       = {12},
  year         = {2010},
}