Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families.
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.
Arason
Adalgeir
A
Department of Pathology, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland. adalgeir@landspitali.is
Gunnarsson
Haukur
H
Johannesdottir
Gudrun
G
Jonasson
Kristjan
K
Bendahl
Pär-Ola
PO
Gillanders
Elizabeth M
EM
Agnarsson
Bjarni A
BA
Jönsson
Göran
G
Pylkäs
Katri
K
Mustonen
Aki
A
Heikkinen
Tuomas
T
Aittomäki
Kristiina
K
Blomqvist
Carl
C
Melin
Beatrice
B
Johannsson
Oskar T H
OT
Møller
Pål
P
Winqvist
Robert
R
Nevanlinna
Heli
H
Borg
Ake
A
Barkardottir
Rosa B
RB
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
D019313:BRCA1 Protein; D024682:BRCA2 Protein