Abstract Colorectal cancer (CRC) causes nearly 50,000 deaths in the United States each year and therefore represents the third leading cause of cancer-related deaths. The identification of susceptibility variants that interact to modulate risk for sporadic CRC would have immense value as a tool to identify individuals with increased genetic predisposition to disease. Polymorphisms in Aurora Kinase A (AURKA) and Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) have been shown to increase CRC risk in human case-control studies. Crosses between mice resistant and susceptible to chemically induced skin cancer have led to the identification of two loci, Skts1 and Skts5, each of which statistically interacts with the Aurka locus to promote skin cancer in a murine model. Using a similar approach, the mouse Ptprj locus has been shown to interact synergistically with the loci Scc5 and Scc13 to increase colon cancer susceptibility. Array comparative genomic hybridization studies in human colorectal tumor DNAs have shown high frequencies of genomic copy number gains or losses at the human orthologs of Skts1, Skts5, Scc5, and Scc13. Our goal is to identify sporadic CRC risk variants and to characterize genetic interactions at the AURKA- and PTPRJ-interacting loci. We hypothesize that the human orthologs of these mouse CRC susceptibility loci will interact genetically with AURKA and PTPRJ to influence CRC risk. By generating normal colon transcriptome data from CRC-susceptible and CRC–resistant mouse strains using RNA-Seq, we prioritized candidate genes on the basis of differential expression, differential splicing or potentially functional polymorphisms. Tagging single nucleotide polymorphisms (tagSNPs) for the human orthologs of these genes were tested for allele-specific imbalance by Sequenom MassARRAY quantitative genotyping of 194 paired human colorectal tumor/non-tumor DNA samples. TagSNPs exhibiting point-wise p-values < 0.1 were further tested in a replication sample set of 296 paired colorectal tumor/non-tumor DNA samples. Among ∼900 tagSNPs tested, 75 polymorphisms reproducibly showed evidence of allele-specific imbalance (point-wise p-values < 0.05). Our data indicate that allele-specific imbalance occurs in candidate genes (e.g. KLF13, HDAC9, FBN2, SNX10 and PRDM5) whose murine orthologs map to cancer susceptibility loci. Our next step is to explore expression patterns of these candidate genes in human colorectal tumor and non-tumor tissues and to investigate the effects of gene silencing or overexpression on critical cancer phenotypes such as proliferation, apoptosis, and migration in mouse and human colon cancer cell lines. Additionally, an ongoing human case-control association study of 6000 colorectal cancer cases and 6000 controls is expected to yield results shortly, which will be presented at the 2013 AACR meeting. Citation Format: Madelyn M. Gerber, Nathan P. Schulz, Mehmet Deveci, Heather L. Hampel, Umit V. Catalyurek, Albert de la Chapelle, Amanda Ewart Toland. Identification of AURKA- and PTPRJ-interacting human colorectal cancer susceptibility alleles. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2998. doi:10.1158/1538-7445.AM2013-2998