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


CONCLUSIONS
Our results show the power increase that SNPs can supply in linkage studies.
Gonzalez-Neira
Anna
A
Genotyping Unit, CeGen, Human Cancer Genetics Programme, Spanish National Cancer Centre, Spain. agonzalez@cnio.es
Rosa-Rosa
Juan Manuel
JM
Osorio
Ana
A
Gonzalez
Emilio
E
Southey
Melissa
M
Sinilnikova
Olga
O
Lynch
Henry
H
Oldenburg
Rogier A
RA
van Asperen
Christi J
CJ
Hoogerbrugge
Nicoline
N
Pita
Guillermo
G
Devilee
Peter
P
Goldgar
David
D
Benitez
Javier
J
D002874:Chromosome Mapping; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide