Whole-genome Linkage Analysis and Sequence Analysis of Candidate Loci in Familial Breast Cancer

Background: Known breast cancer-predisposing genes account for fewer than 25% of all familial breast cancer cases and further studies are required to find the remaining high- and moderate-risk genes. We set-out to couple linkage analysis using microsatellite marker data and sequence analysis of linked regions in 13 non-BRCA1/2 families in order to find novel susceptibility loci and high- penetrant genes. Materials and Methods: Genotyping with 540 fluorescently-labeled microsatellite markers located on the 23 chromosomes at 7.25 cM resolution was used for primary linkage analysis and an additional 40 markers were used for fine-mapping of loci with a logarithm of odds (LOD) or heterogeneity LOD (HLOD) score greater than one. Whole-exome sequencing data of 28 members from all 13 families were used for the bioinformatics sequence analysis on the linked regions of these families. Results: Linkage analysis identified three loci on chromosome 18q as a putative region of interest (overall LOD=1, HLOD=1.2). Sequencing analysis of the three linked regions on 18q and mutation prediction algorithms did reveal three probable damaging variants. Conclusion: Overall, our study identified three weakly linked loci on 18q and three probable damaging variants of interest in the 13 families with breast cancer. first-degree relatives of patients with breast cancer have a two-fold higher risk of breast cancer compared to the general population (1). Even though this could be, at least in part, due to shared environmental or lifestyle factors, twin studies found that up to 30% of all breast cancer cases may be due to genetic factors (2). Nonetheless, only approximately 5% of all breast cancer cases are attributed to the segregation of a germline mutation of a highly penetrant gene within the family (3). The two major high-risk genes are breast cancer 1 and 2 genes BRCA1 and BRCA2, which together account for ~16% of the familial risk of breast cancer, while