Genome-wide linkage scan in Dutch hereditary non-BRCA1/2 breast cancer families identifies 9q21-22 as a putative breast cancer susceptibility locus

Breast cancer accounts for over 20% of all female cancers. A positive family history remains one of the most important risk factors for the disease, with first-degree relatives of patients having a twofold elevated risk. Known breast cancer susceptibility genes such as BRCA1 and BRCA2 explain only 20-25% of this risk, suggesting the existence of other breast cancer susceptibility genes. Here, we report the results of a genome-wide linkage scan in 55 high-risk Dutch breast cancer families with no mutations in BRCA1 and BRCA2. Twenty-two of these families were also part of a previous linkage study by the Breast Cancer Linkage Consortium. In addition, we performed CGH analyses in 61 tumors of these families and 31 sporadic tumors. Three regions were identified with parametric HLOD scores >1, and three with nonparametric LOD scores >1.5. Upon further marker genotyping for the candidate loci, and the addition of another 30 families to the analysis, only the locus on chromosome 9 (9q21-22, marker D9S167) remained significant, with a nonparametric multipoint LOD score of 3.96 (parametric HLOD 0.56, α = 0.18). With CGH analyses we observed preferential copy number loss at BAC RP11-276H19, containing D9S167 in familial tumors as compared to sporadic tumors (P < 0.001). Five candidate genes were selected from the region around D9S167 and their coding regions subjected to direct sequence analysis in 16 probands. No clear pathogenic mutations were found in any of these genes.

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