The human chromosome 9 region orthologous to Mcs5a, a rat composite modifier locus, contains a breast cancer risk allele.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5401 We have used a rat breast cancer model to identify and narrow an orthologous human genomic region for testing in a breast cancer case-control SNP-association study. Mcs5a , one of three subloci identified within the Wistar-Kyoto (WKy) Mcs5 QTL, confers resistance to DMBA-, NMU- and, HER2/ neu -induced mammary carcinomas in the rat. Congenic female rats (WF.WKy line O) with two Mcs5a WKy alleles developed 3.9±0.4, 2.2±0.4, and 9.9±1.1 mammary carcinomas/rat for DMBA, NMU, and HER2/ neu treatments, respectively. The WF.WKy females with two Mcs5a WF alleles averaged 8.9±0.8, 3.8±0.5, and 17.1±1.9 mammary carcinomas/rat when administered DMBA, NMU, or HER2/ neu , respectively. Mcs5a has been fine mapped, using a series of overlapping congenic lines, and shown to be a composite locus consisting of a genetic interaction between at least two adjacent genetic elements ( Mcs5a1 and Mcs5a2 ). Both Mcs5a1 and Mcs5a2 are required to be WKy alleles in order to confer the decreased mammary carcinoma susceptibility phenotype (i.e. the presence of WF alleles at either locus results in abrogation of the resistance phenotype). A recombinant congenic line (B3) from line O that is WKy-homozygous at Mcs5a1, but WF-homozygous at Mcs5a2 averaged 7.6±0.9 DMBA-induced mammary carcinomas/rat. Another line O recombinant congenic line (LL) that is WF-homozygous at Mcs5a1, but WKy-homozygous at Mcs5a2 averaged 7.1±0.5 DMBA-induced mammary carcinomas/rat. These phenotypes were not different from females of each line that were WF-homozygous at both loci and averaged 7.9±0.7 and 8.1±0.7 mammary carcinomas/rat, respectively. These DMBA-susceptible lines, B3 and LL, overlap by ∼400 bp on their opposing, distal and proximal ends. Two additional line O recombinant lines (WW and XX) that overlap by ∼116 Kb at their respective distal and proximal ends within this same genomic region have DMBA-resistance phenotypes similar to the parental Mcs5a line (O). Line WW females averaged 4.3±0.5 and line XX females averaged 5.3±0.3 DMBA-induced mammary carcinomas/rat. Respectively, the Mcs5a1 and Mcs5a2 orthologous regions are localized to 32 and 84 Kb on rat chromosome 5 ; and 30 and 63 Kb on human chromosome 9 . A SNP with a minor allele frequency of 12% in the human Mcs5a2 -region associated with a reduced breast cancer risk in two human case-control populations (n = 12,000) with an odds ratio of 0.86 (CI 0.78-0.94) for heterozygous women. SNPs located in the human Mcs5a1 region are currently being tested for an association to breast cancer.