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BIOLOGICAL SCIENCES / GENETICS
Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk
*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706; Department of Population Health Sciences, University of Wisconsin, Madison, WI 53726; and Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom
Communicated by William F. Dove, University of Wisconsin, Madison, WI, February 23, 2007 (received for review October 31, 2006)
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 (
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.
breast cancer genetics | cancer epidemiology | comparative genomics | noncoding elements | rat models
Author contributions: D.J.S. and S.E.H. contributed equally to this work; D.J.S., S.E.H., J.D.H., A.T.-D., and M.N.G. designed research; D.J.S., S.E.H., B.A.A., Y.Z., J.D.H., K.-S.C., C.B., K.-T.K., R.L., B.P., M.S., A.M.D., and D.F.E. performed research; A.T.-D., C.B., K.-T.K., R.L., B.P., M.S., A.M.D., D.F.E., and B.A.P. contributed new reagents/analytic tools; D.J.S., S.E.H., J.M.H., B.M., P.D.P., and M.N.G. analyzed data; and D.J.S., S.E.H., A.T.-D., and M.N.G. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. DQ901406).
This article contains supporting information online at www.pnas.org/cgi/content/full/0701687104/DC1.
To whom correspondence should be addressed at: McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI 53706. E-mail: gould{at}oncology.wisc.edu
© 2007 by The National Academy of Sciences of the USA
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