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.

Figure 1

Representation of the BRCA1/2 Families Mutation carrier individuals (+) were supposed to be affected members (complete penetrance) and their genotypes were used to obtain dominant parametric LOD scores (HLOD) for each family in either chromosome 13 or chromosome 17. Genotypes from noncarriers individuals (−) were used to observe variations in HLOD scores. When a noncarrier individual was included as an affected member (phenocopy), HLOD score dropped to even negative values in the region that harbors the mutation. When a noncarrier individual is included as a nonaffected member, the increase in HLOD score was not significant.

Figure 2

Representation of LOD Scores for All the Autosomal Chromosomes The y axis represents LOD score values and x axis represents the autosomal chromosomes. The green line represents the nonparametric LOD score (NPL), whereas the blue line represents dominant parametric LOD score (HLOD) score for the 22 autosomal chromosomes. Vertical lines represent the chromosomal boundaries.