RGD Reference Report - Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. - Rat Genome Database

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Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk.

Authors: Samuelson, DJ  Hesselson, SE  Aperavich, BA  Zan, Y  Haag, JD  Trentham-Dietz, A  Hampton, JM  Mau, B  Chen, KS  Baynes, C  Khaw, KT  Luben, R  Perkins, B  Shah, M  Pharoah, PD  Dunning, AM  Easton, DF  Ponder, BA  Gould, MN 
Citation: Samuelson DJ, et al., Proc Natl Acad Sci U S A. 2007 Apr 2; 104(15):6299-304.
RGD ID: 1601189
Pubmed: (View Article at PubMed) PMID:17404222
DOI: Full-text: DOI:10.1073/pnas.0701687104

Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The Mcs5a locus was identified by fine-mapping Mcs5 in a congenic model. Here we characterize the Mcs5a locus, which when homozygous for the Wky allele, reduces mammary cancer risk by 50%. The Mcs5a locus is a compound QTL with at least two noncoding interacting elements: Mcs5a1 and Mcs5a2. The resistance phenotype is only observed in rats carrying at least one copy of the Wky allele of each element on the same chromosome. Mcs5a1 is located within the ubiquitin ligase Fbxo10, whereas Mcs5a2 includes the 5' portion of Frmpd1. Resistant congenic rats show a down-regulation of Fbxo10 in the thymus and an up-regulation of Frmpd1 in the spleen. The association of the Mcs5a1 and Mcs5a2 human orthologs with breast cancer was tested in two population-based breast cancer case-control studies ( approximately 12,000 women). The minor alleles of rs6476643 (MCS5A1) and rs2182317 (MCS5A2) were independently associated with breast cancer risk. The minor allele of rs6476643 increases risk, whereas the rs2182317 minor allele decreases risk. Both alleles have a high population frequency and a low penetrance toward breast cancer risk.



Disease Annotations    

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Fbxo10  (F-box protein 10)
Frmpd1  (FERM and PDZ domain containing 1)

Genes (Mus musculus)
Fbxo10  (F-box protein 10)
Frmpd1  (FERM and PDZ domain containing 1)

Genes (Homo sapiens)
FBXO10  (F-box protein 10)
FRMPD1  (FERM and PDZ domain containing 1)

QTLs
Mcs23  (Mammary carcinoma susceptibility QTL 23)
Mcs24  (Mammary carcinoma susceptibility QTL 24)

Objects referenced in this article
QTL Mcs12 Mammary carcinoma susceptibility QTL 12 Rattus norvegicus
QTL Mcs5 Mammary carcinoma susceptibility QTL 5 Rattus norvegicus

Additional Information