1. Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6299-304. Epub 2007 Apr 2.
Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that
associate with breast cancer risk.
Samuelson DJ(1), 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.
Author information:
(1)McArdle Laboratory for Cancer Research, Department of Oncology, University of
Wisconsin, Madison, WI 53706, USA.
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.
PMCID: PMC1847458
PMID: 17404222 [PubMed - indexed for MEDLINE]
PUBMED: 17404222
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