A Breast Cancer Candidate Locus at 6q Narrowed to 6q15-q21

Abstract

Although a number of high-risk breast cancer genes have been identified, including BRCA1 and BRCA2, the risk profile of many high-risk families cannot be explained using known breast cancer genes. Previously, we have shown strong indications of new breast cancer risk loci at chromosomes 2p, 6q, and 14q in a family of six generations including 10 breast cancer cases. In this study, we identified and traced four new family branches descending from siblings of the parents in the top generation of the studied family. One distantly related branch included four breast cancer cases, two of whom were diagnosed at age < 45 years. DNA samples from the cases were typed at selected polymorphic markers from all three chromosome loci, to test identical origin of the haplotypes. All four cases were shown to segregate a common 6q haplotype with a region identical to the previously identified 6q haplotype. The data strongly support a new breast cancer locus at 6q, and narrow it down to a 17 MB interval at 6q15-q21.

Keywords: hereditary breast cancer; non-BRCA1/2; oligogenic cancer susceptibility.

Figure 1

Extended pedigree tracing showing the narrowed candidate region at chromosome 6q. Not all unaffected family members are shown, and the pedigree is somewhat distorted in order to avoid recognition. The upper panel shows the extended pedigree of family 70234 [4], where half-filled symbols denote diagnosis of BC (with approximate ages shown under the symbols) and full black filling denotes also ovarian cancer (ov) as well as BC. Symbols with a filled corner indicate diagnosis of prostatic or other cancers. Circles refer to females and boxes to males. Asterisk refers to the grandfather of two sisters, who had a haplotype identical to the remaining two cases (his nieces) in the new branch. The breast-ovarian cancer case in generation VI is also a BRCA2-mutation carrier and therefore not included in the count of 6q-haplotype carriers among BC cases in this report. The lower panel shows haplotype-contained alleles of analyzed markers, together with their allele frequencies in Icelandic controls. Alleles are coded with a, c, g, or t in case of rs-markers, and with these or other lower case letters in case of microsatellite markers (after selecting the codes for each marker by pairing alphabetical order with increasing population allele sizes). Alleles that are identical in all genotyped affected family members are highlighted in yellow.