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Open Access Highly Accessed Research article

Genomewide high-density SNP linkage analysis of non-BRCA1/2 breast cancer families identifies various candidate regions and has greater power than microsatellite studies

Anna Gonzalez-Neira1*, Juan Manuel Rosa-Rosa2, Ana Osorio2, Emilio Gonzalez1, Melissa Southey3, Olga Sinilnikova4, Henry Lynch5, Rogier A Oldenburg67, Christi J van Asperen6, Nicoline Hoogerbrugge8, Guillermo Pita1, Peter Devilee109, David Goldgar11 and Javier Benitez1122

Author Affiliations

1 Genotyping Unit. CeGen. Human Cancer Genetics Programme, Spanish National Cancer Centre, Spain

2 Human Genetics Group. Human Cancer Genetics Programme, Spanish National Cancer Centre, Spain

3 Genetic Cancer Susceptibility Group, IARC, Lyon, France

4 Plate-forme Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon, France

5 Creighton University, Omaha, Nebraska, USA

6 Dept. Of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

7 Dept. Of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands

8 Department of Human Genetics, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands

9 Dept. Of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

10 Dept. Of Pathology, Leiden University Medical Center, Leiden, The Netherlands

11 Genetic Epidemiology Unit, IARC and Department of Dermatology, University of Utah, USA

12 Centre for Biomedical Research in Rare Diseases (CIBER-ER), Madrid, Spain

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BMC Genomics 2007, 8:299  doi:10.1186/1471-2164-8-299

Published: 30 August 2007

Abstract

Background

The recent development of new high-throughput technologies for SNP genotyping has opened the possibility of taking a genome-wide linkage approach to the search for new candidate genes involved in heredity diseases. The two major breast cancer susceptibility genes BRCA1 and BRCA2 are involved in 30% of hereditary breast cancer cases, but the discovery of additional breast cancer predisposition genes for the non-BRCA1/2 breast cancer families has so far been unsuccessful.

Results

In order to evaluate the power improvement provided by using SNP markers in a real situation, we have performed a whole genome screen of 19 non-BRCA1/2 breast cancer families using 4720 genomewide SNPs with Illumina technology (Illumina's Linkage III Panel), with an average distance of 615 Kb/SNP. We identified six regions on chromosomes 2, 3, 4, 7, 11 and 14 as candidates to contain genes involved in breast cancer susceptibility, and additional fine mapping genotyping using microsatellite markers around linkage peaks confirmed five of them, excluding the region on chromosome 3. These results were consistent in analyses that excluded SNPs in high linkage disequilibrium. The results were compared with those obtained previously using a 10 cM microsatellite scan (STR-GWS) and we found lower or not significant linkage signals with STR-GWS data compared to SNP data in all cases.

Conclusion

Our results show the power increase that SNPs can supply in linkage studies.