Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer- associated variants

被引：48

作者：

Peltekova, Vanya D. ^{[1
]}

Lemire, Mathieu ^{[1
]}

Qazi, Aamer M. ^{[1
]}

Zaidi, Syed H. E. ^{[1
]}

Trinh, Quang M. ^{[1
]}

Bielecki, Ryszard ^{[2
]}

Rogers, Marianne ^{[3
]}

Hodgson, Lyndsey ^{[1
]}

Wang, Mike ^{[1
]}

D'Souza, David J. A. ^{[1
]}

Zandi, Sasan ^{[4
]}

Chong, Taryne ^{[1
]}

Kwan, Jennifer Y. Y. ^{[1
]}

Kozak, Krystian ^{[1
]}

De Borja, Richard ^{[1
]}

Timms, Lee ^{[1
]}

Rangrej, Jagadish ^{[1
]}

Volar, Milica ^{[1
]}

Chan-Seng-Yue, Michelle ^{[1
]}

Beck, Timothy ^{[1
]}

Ash, Colleen ^{[2
]}

Lee, Shawna ^{[1
]}

Wang, Jianxin ^{[1
]}

Boutros, Paul C. ^{[1
,5
]}

Stein, Lincoln D. ^{[1
,6
]}

Dick, John E. ^{[4
,5
,6
]}

Gryfe, Robert ^{[2
,7
]}

McPherson, John D. ^{[1
,5
]}

Zanke, Brent W. ^{[8
]}

Pollett, Aaron ^{[3
]}

Gallinger, Steven ^{[2
,9
]}

Hudson, Thomas J. ^{[1
,5
,6
]}

机构：

[1] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

[2] Samuel Lunenfeld Res Inst, Toronto, ON M5S 1X5, Canada

[3] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada

[4] Univ Hlth Network, Campbell Family Inst Canc Res, Ontario Canc Inst, Div Stem Cell & Dev Biol, Toronto, ON M5G 2M9, Canada

[5] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada

[6] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada

[7] Mt Sinai Hosp, Dept Surg, Toronto, ON M5G 1X1, Canada

[8] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON K1Y 4E9, Canada

[9] Toronto Gen Hosp, Div Gen Surg, Toronto, ON M5G 2C4, Canada

来源：

INTERNATIONAL JOURNAL OF CANCER | 2014年 / 134卷 / 10期

关键词：

genome-wide association study; genetic risk factors; colon cancer; tumor microenvironment; GENOME-WIDE ASSOCIATION; MICROSATELLITE INSTABILITY; SUSCEPTIBILITY LOCI; MAST-CELLS; RISK; RS6983267; TUMORS; SHOWS; LINE;

D O I：

10.1002/ijc.28557

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 x 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. What's new? Genome-wide association studies have identified genomic loci associated with increased cancer risk, but the precise identification of the genes supporting cancer development within these loci remains challenging. The authors performed high-resolution mapping of a region on chromosome 11q23 previously associated with colorectal cancer predisposition. They identified COLCA1 and COLCA2, two coordinately regulated genes for which transcript and protein expression correlated with the presence or absence of the single-nucleotide polymorphism (SNP) identified in the region. In addition, the presence of the SNP as well as expression levels of the candidate genes correlated with a characteristic histological pattern of lymphocyte infiltration in the lamina propria of the colon tissue. These studies link colon cancer risk with immune pathways providing new opportunities for improved colon cancer diagnostic tools, novel predictive biomarkers, and potential therapeutic strategies modulating the tumor microenvironment.

引用

页码：2330 / 2341

页数：12

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