title: 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.
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH.
authors.forename: Madelyn M
authors.initials: MM
authors.lastname: Gerber
authors.affiliation: Division of Human Genetics, Department of Internal Medicine, The Ohio State Wexner Medical Center, Columbus, OH.|The OSU Comprehensive Cancer Center, Columbus, OH.
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.affiliation: The OSU Comprehensive Cancer Center, Columbus, OH.|Department of Pathology, The Ohio State Wexner Medical Center, Columbus, OH.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhou
authors.affiliation: Department of Psychiatry, University of Illinois Health System, Chicago, IL.|Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, OH.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Schulz
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH.
authors.forename: Adam
authors.initials: A
authors.lastname: Suhy
authors.affiliation: Biomedical Informatics, Computer Science and Engineering, The Ohio State University, Columbus, OH.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Deveci
authors.affiliation: Biomedical Informatics, Electrical and Computer Engineering, the Ohio State University, Columbus, OH.
authors.forename: Ümit V
authors.initials: ÜV
authors.lastname: Çatalyürek
authors.affiliation: Division of Human Genetics, Department of Internal Medicine, The Ohio State Wexner Medical Center, Columbus, OH.|The OSU Comprehensive Cancer Center, Columbus, OH.|Department of Molecular Virology, Immunology and Medical Genetics, the Ohio State University, Columbus, OH.
authors.forename: Amanda
authors.initials: A
authors.lastname: Ewart Toland
mesh_terms: D000483:Alleles; D022981:Allelic Imbalance; D000818:Animals; D043171:Chromosomal Instability / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017423:Sequence Analysis, RNA / Q000379:methods
keywords: Scc13; Scc4; Scc5; allele-specific imbalance; colon cancer susceptibility loci; colorectal cancer