Tumor and Stem Cell Biology Rat Mcs1b Is Concordant to the Genome-Wide Association- Identified Breast Cancer Risk Locus at Human 5q11.2 and MIER3 is a Candidate Cancer Susceptibility Gene

نویسندگان

  • Aaron D. denDekker
  • Xin Xu
  • M. Derek Vaughn
  • Aaron H. Puckett
  • Louis L. Gardner
  • Courtney J. Lambring
  • David J. Samuelson
چکیده

Low-penetrance alleles associated with breast cancer risk have been identified in population-based studies. Most risk loci contain either no or multiple potential candidate genes. Rat mammary carcinoma susceptibility 1b (Mcs1b) is a quantitative trait locus on RN02 that confers decreased susceptibility when Copenhagen (COP)resistant alleles are introgressed into a Wistar Furth (WF)-susceptible genome. Five WF.COP congenic lines containing COP RN02 segments were compared. One line developed an average of 3.4 2.0 and 5.5 3.6 mammary carcinomas per rat SD when females were Mcs1b-resistant homozygous and Mcs1b heterozygous, respectively. These phenotypes were significantly different from susceptible genotype littermates (7.8 3.1 mean mammary carcinomas per rat SD, P1⁄4 0.0001 and P1⁄4 0.0413, respectively). All other congenic lines tested were susceptible. Thus, Mcs1b was narrowed to 1.8 Mb of RN02 between genetic markers ENSRNOSNP2740854 and g2UL2-27. Mammary gland-graft carcinoma susceptibility assays were used to determine that donor (P1⁄4 0.0019), but not recipient Mcs1b genotype (P 1⁄4 0.9381), was associated with ectopic mammary carcinoma outcome. Rat Mcs1b contains sequence orthologous to human 5q11.2, a breast cancer susceptibility locus identified in multiple genome-wide association studies. Human/ratMAP3K1/Map3k1 and mesoderm induction early response (MIER; MIER3)/MIER3 are within these orthologous segments. We identifiedMIER3 as a candidateMcs1b gene based on 4.5-fold highermammary gland levels ofMIER3 transcripts in susceptible comparedwithMcs1b-resistant females. These data suggest that the human 5q11.2 breast cancer risk allele marked by rs889312 is mammary gland autonomous, andMIER3 is a candidate breast cancer susceptibility gene.Cancer Res; 72(22); 6002–12. 2012AACR.

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Rat Mcs1b is concordant to the genome-wide association-identified breast cancer risk locus at human 5q11.2 and MIER3 is a candidate cancer susceptibility gene.

Low-penetrance alleles associated with breast cancer risk have been identified in population-based studies. Most risk loci contain either no or multiple potential candidate genes. Rat mammary carcinoma susceptibility 1b (Mcs1b) is a quantitative trait locus on RN02 that confers decreased susceptibility when Copenhagen (COP)-resistant alleles are introgressed into a Wistar Furth (WF)-susceptible...

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تاریخ انتشار 2012