title: Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk.
abstract: 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.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Samuelson
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Hesselson
authors.forename: Beth A
authors.initials: BA
authors.lastname: Aperavich
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Zan
authors.forename: Jill D
authors.initials: JD
authors.lastname: Haag
authors.forename: Amy
authors.initials: A
authors.lastname: Trentham-Dietz
authors.forename: John M
authors.initials: JM
authors.lastname: Hampton
authors.forename: Bob
authors.initials: B
authors.lastname: Mau
authors.forename: Kai-Shun
authors.initials: KS
authors.lastname: Chen
authors.forename: Caroline
authors.initials: C
authors.lastname: Baynes
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.forename: Barbara
authors.initials: B
authors.lastname: Perkins
authors.forename: Mitul
authors.initials: M
authors.lastname: Shah
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Doug F
authors.initials: DF
authors.lastname: Easton
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ponder
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gould
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019295:Computational Biology; D003433:Crosses, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051381:Rats; D011920:Rats, Inbred WF; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D006113:United Kingdom; D020506:Untranslated Regions / Q000235:genetics; D014922:Wisconsin
chemical_list: D020506:Untranslated Regions