Open Access Highly Accessed Research article

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

Adalgeir Arason12*, Haukur Gunnarsson1, Gudrun Johannesdottir1, Kristjan Jonasson3, Pär-Ola Bendahl4, Elizabeth M Gillanders5, Bjarni A Agnarsson12, Göran Jönsson4, Katri Pylkäs6, Aki Mustonen6, Tuomas Heikkinen7, Kristiina Aittomäki8, Carl Blomqvist9, Beatrice Melin10, Oskar TH Johannsson112, Pål Møller12, Robert Winqvist6, Heli Nevanlinna7, Åke Borg4 and Rosa B Barkardottir12

Author Affiliations

1 Department of Pathology, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland

2 Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland

3 Faculty of Engineering and Natural Sciences, University of Iceland, Hjardarhaga 2-4, 107 Reykjavik, Iceland

4 Department of Oncology, Clinical Sciences Lund, Lund University, SE 221 85 Lund, Sweden

5 Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive, Suite 1200, Baltimore, MD 21224, USA

6 Laboratory of Cancer Genetics, Department of Clinical Genetics and Biocenter Oulu, University of Oulu, Oulu University Hospital, 90220 Oulu, Finland

7 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. BOX 700, 00029 HUS, Helsinki, Finland

8 Department of Clinical Genetics, Helsinki University Central Hospital, P.O. BOX 140, 00029 HUS, Helsinki, Finland

9 Department of Oncology, Helsinki University Central Hospital, P.O. BOX 180, 00029 HUS, Helsinki, Finland

10 Department of Radiation Sciences, Umeå University, 901 85 Umeå, Sweden

11 Department of Oncology, 20A, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland

12 Section of Inherited Cancer, Oslo University Hospital, 0310 Oslo, Norway

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Breast Cancer Research 2010, 12:R50  doi:10.1186/bcr2608

Published: 16 July 2010

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.