title: Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Pathology, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland. adalgeir@landspitali.is
authors.forename: Adalgeir
authors.initials: A
authors.lastname: Arason
authors.forename: Haukur
authors.initials: H
authors.lastname: Gunnarsson
authors.forename: Gudrun
authors.initials: G
authors.lastname: Johannesdottir
authors.forename: Kristjan
authors.initials: K
authors.lastname: Jonasson
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Gillanders
authors.forename: Bjarni A
authors.initials: BA
authors.lastname: Agnarsson
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Aki
authors.initials: A
authors.lastname: Mustonen
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Beatrice
authors.initials: B
authors.lastname: Melin
authors.forename: Oskar T H
authors.initials: OT
authors.lastname: Johannsson
authors.forename: Pål
authors.initials: P
authors.lastname: Møller
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Rosa B
authors.initials: RB
authors.lastname: Barkardottir
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006239:Haplotypes; D006801:Humans; D007055:Iceland; D008126:Lod Score; D008297:Male; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D010375:Pedigree
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein