Allele-specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

Abstract

Colorectal cancer (CRC) can be classified into different types. Chromosomal instable (CIN) colon cancers are thought to be the most common type of colon cancer. The risk of developing a CIN-related CRC is due in part to inherited risk factors. Genome-wide association studies have yielded over 40 single nucleotide polymorphisms (SNPs) associated with CRC risk, but these only account for a subset of risk alleles. Some of this missing heritability may be due to gene-gene interactions. We developed a strategy to identify interacting candidate genes/loci for CRC risk that utilizes both linkage and RNA-seq data from mouse models in combination with allele-specific imbalance (ASI) studies in human tumors. We applied our strategy to three previously identified CRC susceptibility loci in the mouse that show evidence of genetic interaction: Scc4, Scc5 and Scc13. 525 SNPs from genes showing differential expression in the mouse and/or a previous role in cancer from the literature were evaluated for allele-specific imbalance in 194 paired human normal/tumor DNAs from CIN-related CRCs. One hundred three SNPs showing suggestive evidence of ASI (31 variants with uncorrected p values < 0.05) were genotyped in a validation set of 296 paired DNAs. Two variants in SNX10 (SCC13) showed significant evidence of allelic selection after multiple comparisons testing. Future studies will evaluate the role of these variants in combination with interacting genetic partners in colon cancer risk in mouse and humans.

Keywords: Scc13; Scc4; Scc5; allele-specific imbalance; colon cancer susceptibility loci; colorectal cancer.

Figure 1:. Experiment Design

Data from three sources were used to identify candidate susceptibility genes for CRC. RNA-seq data from normal colons was generated from cancer susceptible STS/A and cancer resistant Balb/cHeA mice. aCGH data from human CRCs was used to confirm that SCC loci for study were showing copy number changes. Allele-specific imbalance (ASI) studies were completed on paired normal and colon tumor DNAs for the orthologous human loci to Scc4, Scc5 and Scc13.