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Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer ( Scc ) loci
Author(s) -
Gerber Madelyn M.,
Hampel Heather,
Zhou XiaoPing,
Schulz Nathan P.,
Suhy Adam,
Deveci Mehmet,
Çatalyürek Ümit V.,
Ewart Toland Amanda
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29599
Subject(s) - allele , single nucleotide polymorphism , genetics , biology , missing heritability problem , colorectal cancer , gene , cancer , genome wide association study , genetic association , genetic linkage , candidate gene , genotype
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.