title: Genome-wide linkage scan reveals three putative breast-cancer-susceptibility loci.
abstract: Despite all the research efforts made during the last few decades, most of the cases of families with breast cancer remain unexplained. Mutations in BRCA1 and BRCA2, and in other breast-cancer-susceptibility genes, account for about 25% of familial breast cancer. Linkage studies have failed to identify other breast-cancer-susceptibility genes. The selection criteria of the families, differences in the population background, or clinical and genetic heterogeneity, among other factors, might determine the power to detect the linkage signal. We have performed a SNP-based linkage scan with a total of 6000 SNP markers across the genome in 41 breast-cancer Spanish families, with an average of four breast-cancer cases per family not associated with BRCA1 or BRCA2 germline mutations. In addition, we have included three BRCA-positive families to test the power in linkage detection from a low-complexity family in which a high-penetrance mutation segregates. We have identified three regions of interest, located on 3q25, 6q24, and 21q22. The two former regions showed a suggestive linkage signal (HLOD scores 3.01 and 2.26, respectively), and the latter region showed a significant linkage signal (HLOD score 3.55). Moreover, we found that a subset of 13 families with bilateral breast cancer presented a HLOD of 3.13 on the 3q25 region. Our results suggest that several variables must be taken into account before performing a linkage study in familial breast cancer because of the high heterogeneity within non-BRCA1/2 families. Phenotypic and geographic homogeneity could be the most important factors.
authors.affiliation: Human Cancer Genetics Programme, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Rosa-Rosa
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Gemma
authors.initials: G
authors.lastname: Llort
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramón y Cajal
authors.forename: Orland
authors.initials: O
authors.lastname: Díez
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Tejada
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D002893:Chromosomes, Human, Pair 3; D002896:Chromosomes, Human, Pair 6; D005190:Family; D005260:Female; D007839:Functional Laterality; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree
chemical_list: D005819:Genetic Markers