title: Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.
abstract: A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways.
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
authors.forename: Vanya D
authors.initials: VD
authors.lastname: Peltekova
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.forename: Aamer M
authors.initials: AM
authors.lastname: Qazi
authors.forename: Syed H E
authors.initials: SH
authors.lastname: Zaidi
authors.forename: Quang M
authors.initials: QM
authors.lastname: Trinh
authors.forename: Ryszard
authors.initials: R
authors.lastname: Bielecki
authors.forename: Marianne
authors.initials: M
authors.lastname: Rogers
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Hodgson
authors.forename: Mike
authors.initials: M
authors.lastname: Wang
authors.forename: David J A
authors.initials: DJ
authors.lastname: D'Souza
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.forename: Taryne
authors.initials: T
authors.lastname: Chong
authors.forename: Jennifer Y Y
authors.initials: JY
authors.lastname: Kwan
authors.forename: Krystian
authors.initials: K
authors.lastname: Kozak
authors.forename: Richard
authors.initials: R
authors.lastname: De Borja
authors.forename: Lee
authors.initials: L
authors.lastname: Timms
authors.forename: Jagadish
authors.initials: J
authors.lastname: Rangrej
authors.forename: Milica
authors.initials: M
authors.lastname: Volar
authors.forename: Michelle
authors.initials: M
authors.lastname: Chan-Seng-Yue
authors.forename: Timothy
authors.initials: T
authors.lastname: Beck
authors.forename: Colleen
authors.initials: C
authors.lastname: Ash
authors.forename: Shawna
authors.initials: S
authors.lastname: Lee
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wang
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Stein
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Robert
authors.initials: R
authors.lastname: Gryfe
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.forename: Brent W
authors.initials: BW
authors.lastname: Zanke
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000145:classification / Q000235:genetics*; D045325:HCT116 Cells; D057809:HEK293 Cells; D018922:HL-60 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007107:Immune System / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D019169:Jurkat Cells; D020014:K562 Cells; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012313:RNA; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D020298:U937 Cells
chemical_list: D009363:Neoplasm Proteins; D012313:RNA; C588266:COLCA1 protein, human; C588267:POU2AF3 protein, human
keywords: colon cancer; genetic risk factors; genome-wide association study; tumor microenvironment