title: Positional mapping and candidate gene analysis of the mouse Ccs3 locus that regulates differential susceptibility to carcinogen-induced colorectal cancer.
abstract: The Ccs3 locus on mouse chromosome 3 regulates differential susceptibility of A/J (A, susceptible) and C57BL/6J (B6, resistant) mouse strains to chemically-induced colorectal cancer (CRC). Here, we report the high-resolution positional mapping of the gene underlying the Ccs3 effect. Using phenotype/genotype correlation in a series of 33 AcB/BcA recombinant congenic mouse strains, as well as in groups of backcross populations bearing unique recombinant chromosomes for the interval, and in subcongenic strains, we have delineated the maximum size of the Ccs3 physical interval to a ∼2.15 Mb segment. This interval contains 12 annotated transcripts. Sequencing of positional candidates in A and B6 identified many either low-priority coding changes or non-protein coding variants. We found a unique copy number variant (CNV) in intron 15 of the Nfkb1 gene. The CNV consists of two copies of a 54 bp sequence immediately adjacent to the exon 15 splice site, while only one copy is found in CRC-susceptible A. The Nfkb1 protein (p105/p50) expression is much reduced in A tumors compared to normal A colonic epithelium as analyzed by immunohistochemistry. Studies in primary macrophages from A and B6 mice demonstrate a marked differential activation of the NfκB pathway by lipopolysaccharide (kinetics of stimulation and maximum levels of phosphorylated IκBα), with a more robust activation being associated with resistance to CRC. NfκB has been previously implicated in regulating homeostasis and inflammatory response in the intestinal mucosa. The interval contains another positional candidate Slc39a8 that is differentially expressed in A vs B6 colons, and that has recently been associated in CRC tumor aggressiveness in humans.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Meunier
authors.forename: Lauren
authors.initials: L
authors.lastname: Van Der Kraak
authors.forename: Claire
authors.initials: C
authors.lastname: Turbide
authors.forename: Normand
authors.initials: N
authors.lastname: Groulx
authors.forename: Ingrid
authors.initials: I
authors.lastname: Labouba
authors.forename: Pablo
authors.initials: P
authors.lastname: Cingolani
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blanchette
authors.forename: Garabet
authors.initials: G
authors.lastname: Yeretssian
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006824:Hybridization, Genetic; D007178:Inbreeding; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity
chemical_list: D002273:Carcinogens; D052002:NF-kappa B p50 Subunit