Abstract
Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
Highlights
5% of all breast cancer cases are attributed to the segregation of germline mutations in high penetrance genes within families [1,2,3]
In an attempt to identify new breast cancer susceptibility loci, a genome-wide linkage analysis was conducted in 96 non-BRCA1/2 families with breast or breast-ovarian cancer
There were few individuals available for study and no overall significant positive logarithm of odds (LOD), heterogeneity LOD (HLOD) or nonparametric linkage LOD (NPL LOD) scores were obtained for any chromosome [25]
Summary
5% of all breast cancer cases are attributed to the segregation of germline mutations in high penetrance genes within families [1,2,3]. Linkage analysis followed by positional cloning has been successfully applied to identify the high penetrance breast cancer susceptibility genes BRCA1 and BRCA2 [5, 6]. Genome-wide association studies, mostly within the Breast Cancer Association Consortium (BCAC), have identified low-penetrance alleles that explain part of the remaining familial breast cancer risk [23]. Over the past a few years, whole-exome sequencing has been utilized to search for novel breast cancer susceptibility genes, assuming that the missing breast cancer heritability can partly be attributed to rare risk alleles segregating in families in an autosomal-dominant pattern (reviewed in [24]). We have used linkage and association studies in familial and sporadic breast cancer to define a breast cancer susceptibility locus on chromosome 6q
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