Epistatic effect of TLR3 and cGAS-STING-IKKε-TBK1-IFN signaling variants on colorectal cancer risk
Language English Country United States Media print-electronic
Document type Journal Article, Observational Study, Research Support, Non-U.S. Gov't
PubMed
31869529
PubMed Central
PMC7013077
DOI
10.1002/cam4.2804
Knihovny.cz E-resources
- Keywords
- CRC, interaction, polygenic-risk-score, risk,
- MeSH
- Adult MeSH
- Epistasis, Genetic * MeSH
- Genotyping Techniques MeSH
- Interferons genetics MeSH
- Polymorphism, Single Nucleotide MeSH
- Carcinogenesis genetics MeSH
- I-kappa B Kinase genetics MeSH
- Cohort Studies MeSH
- Colon diagnostic imaging pathology MeSH
- Colonoscopy MeSH
- Colorectal Neoplasms diagnosis genetics pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Membrane Proteins genetics MeSH
- Adolescent MeSH
- Young Adult MeSH
- Nucleotidyltransferases genetics MeSH
- Protein Serine-Threonine Kinases genetics MeSH
- Gene Expression Regulation, Neoplastic * MeSH
- Rectum diagnostic imaging pathology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Signal Transduction genetics MeSH
- Case-Control Studies MeSH
- Toll-Like Receptor 3 genetics MeSH
- Computational Biology MeSH
- Healthy Volunteers MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- cGAS protein, human MeSH Browser
- IKBKE protein, human MeSH Browser
- Interferons MeSH
- I-kappa B Kinase MeSH
- Membrane Proteins MeSH
- Nucleotidyltransferases MeSH
- Protein Serine-Threonine Kinases MeSH
- STING1 protein, human MeSH Browser
- TBK1 protein, human MeSH Browser
- TLR3 protein, human MeSH Browser
- Toll-Like Receptor 3 MeSH
OBJECTIVE: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. METHODS: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. RESULTS: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. CONCLUSIONS: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.
Center for Primary Health Care Research Clinical Research Center Lund University Malmö Sweden
Department of Internal Medicine 5 University of Heidelberg Heidelberg Germany
Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany
Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany
Faculty of Medicine in Pilsen Biomedical Center Charles University Prague Pilsen Czech Republic
Hopp Children's Cancer Center Heidelberg Germany
Molecular and Genetic Epidemiology Italian Institute for Genomic Medicine Turin Italy
See more in PubMed
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394‐424. PubMed
Hong SN. Genetic and epigenetic alterations of colorectal cancer. Intest Res. 2018;16(3):327‐337. PubMed PMC
Frank C, Sundquist J, Yu H, Hemminki A, Hemminki K. Concordant and discordant familial cancer: familial risks, proportions and population impact. Int J Cancer. 2017;140(7):1510‐1516. PubMed
Sud A, Kinnersley B, Houlston RS. Genome‐wide association studies of cancer: current insights and future perspectives. Nat Rev Cancer. 2017;17(11):692‐704. PubMed
Huyghe JR, Bien SA, Harrison TA, et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet. 2019;51(1):76‐87. PubMed PMC
Hua RX, Zhuo ZJ, Zhu J, et al. XPG gene polymorphisms contribute to colorectal cancer susceptibility: a two‐stage case‐control study. J Cancer. 2016;7(12):1731‐1739. PubMed PMC
Hua R‐X, Zhu J, Jiang D‐H, et al. Association of XPC gene polymorphisms with colorectal cancer risk in a southern chinese population: a case‐control study and meta‐analysis. Genes. 2016;7(10):73. PubMed PMC
Sun J, Kato I. Gut microbiota, inflammation and colorectal cancer. Genes Dis. 2016;3(2):130‐143. PubMed PMC
Lukas M. Inflammatory bowel disease as a risk factor for colorectal cancer. Dig Dis. 2010;28(4–5):619‐624. PubMed
Tilg H, Adolph TE, Gerner RR, Moschen AR. The intestinal microbiota in colorectal cancer. Cancer Cell. 2018;33(6):954‐964. PubMed
Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775‐787. PubMed
Weber AN, Forsti A. Toll‐like receptor genetic variants and colorectal cancer. Oncoimmunology. 2014;3(1):e27763. PubMed PMC
Kaisho T, Akira S. Regulation of dendritic cell function through Toll‐like receptors. Curr Mol Med. 2003;3(4):373‐385. PubMed
Kawai T, Akira S. Regulation of innate immune signalling pathways by the tripartite motif (TRIM) family proteins. EMBO Mol Med. 2011;3(9):513‐527. PubMed PMC
Zhao GN, Jiang DS, Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. Biochim Biophys Acta. 2015;1852(2):365‐378. PubMed
Kawai T, Akira S. Toll‐like receptor and RIG‐I‐like receptor signaling. Ann N Y Acad Sci. 2008;1143:1‐20. PubMed
Schulz O, Diebold SS, Chen M, et al. Toll‐like receptor 3 promotes cross‐priming to virus‐infected cells. Nature. 2005;433(7028):887‐892. PubMed
Hsia HC, Hutti JE, Baldwin AS. Cytosolic DNA promotes signal transducer and activator of transcription 3 (STAT3) phosphorylation by TANK‐binding kinase 1 (TBK1) to restrain STAT3 activity. J Biol Chem. 2017;292(13):5405‐5417. PubMed PMC
Yang CA, Huang HY, Chang YS, Lin CL, Lai IL, Chang JG. DNA‐sensing and nuclease gene expressions as markers for colorectal cancer progression. Oncology. 2017;92(2):115‐124. PubMed
Bose D. cGAS/STING pathway in cancer: Jekyll and Hyde story of cancer immune response. Int J Mol Sci. 2017;18(11):2456. PubMed PMC
Nojiri K, Sugimoto K, Shiraki K, et al. The expression and function of Toll‐like receptors 3 and 9 in human colon carcinoma. Oncol Rep. 2013;29(5):1737‐1743. PubMed
Niedzielska I, Orawczyk T, Ziaja K, et al. Toll‐like receptors and the tendency of normal mucous membrane to transform to polyp or colorectal cancer. J Physiol Pharmacol. 2009;1:65‐71. PubMed
Slattery ML, Herrick JS, Bondurant KL, Wolff RK. Toll‐like receptor genes and their association with colon and rectal cancer development and prognosis. Int J Cancer. 2012;130(12):2974‐2980. PubMed PMC
Castro FA, Försti A, Buch S, et al. TLR‐3 polymorphism is an independent prognostic marker for stage II colorectal cancer. Eur J Cancer. 2011;47(8):1203‐1210. PubMed
Lu S, Pardini B, Cheng B, et al. Single nucleotide polymorphisms within interferon signaling pathway genes are associated with colorectal cancer susceptibility and survival. PLoS ONE. 2014;9(10):e111061. PubMed PMC
Catalano C, da Silva Filho MI, Frank C, et al. Investigation of single and synergic effects of NLRC5 and PD‐L1 variants on the risk of colorectal cancer. PLoS ONE. 2018;13(2):e0192385. PubMed PMC
Carrai M, Campa D, Vodicka P, et al. Association between taste receptor (TAS) genes and the perception of wine characteristics. Sci Rep. 2017;7(1):9239. PubMed PMC
Wacholder S, Chanock S, Garcia‐Closas M, El Ghormli L, Rothman N. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96(6):434‐442. PubMed PMC
Bednarczyk M, Muc‐Wierzgon M, Walkiewicz K, Kokot T, Fatyga E, Mazurek U. Profile of gene expression of TLR‐signaling pathways in colorectal cancer tissues. Int J Immunopathol Pharmacol. 2017;30(3):322‐326. PubMed PMC
Diner E, Burdette D, Wilson S, et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 2013;3(5):1355‐1361. PubMed PMC
Yang H, Wang H, Ren J, Chen Q, Chen ZJ. cGAS is essential for cellular senescence. Proc Natl Acad Sci U S A. 2017;114(23):E4612‐E4620. PubMed PMC
Schmit SL, Edlund CK, Schumacher FR, et al. Novel common genetic susceptibility loci for colorectal cancer. J Natl Cancer Inst. 2018;111(2):146‐157. PubMed PMC
Frampton MJE, Law P, Litchfield K, et al. Implications of polygenic risk for personalised colorectal cancer screening. Ann Oncol. 2016;27(3):429‐434. PubMed
Westra H‐J, Peters MJ, Esko T, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45(10):1238‐1243. PubMed PMC
Esteban‐Jurado C, Garre P, Vila M, et al. New genes emerging for colorectal cancer predisposition. World J Gastroenterol. 2014;20(8):1961‐1971. PubMed PMC
Valle L, Hernández‐Illán E, Bellido F, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet. 2014;23(13):3506‐3512. PubMed
Jing H, Lee S. NF‐kappaB in cellular senescence and cancer treatment. Mol Cells. 2014;37(3):189‐195. PubMed PMC
Basseres DS, Baldwin AS. Nuclear factor‐kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene. 2006;25(51):6817‐6830. PubMed
Hassanzadeh P. Colorectal cancer and NF‐kappaB signaling pathway. Gastroenterol Hepatol Bed Bench. 2011;4(3):127‐132. PubMed PMC
Dev A, Iyer S, Razani B, Cheng G. NF‐kappaB and innate immunity. Curr Top Microbiol Immunol. 2011;349:115‐143. PubMed
Myung D‐S, Park Y‐L, Kim N, et al. Expression of early growth response‐1 in colorectal cancer and its relation to tumor cell proliferation and apoptosis. Oncol Rep. 2014;31(2):788‐794. PubMed
Chinnappan D, Xiao D, Ratnasari A, Andry C, King TC, Weber HC. Transcription factor YY1 expression in human gastrointestinal cancer cells. Int J Oncol. 2009;34(5):1417‐1423. PubMed
Punkenburg E, Vogler T, Büttner M, et al. Batf‐dependent Th17 cells critically regulate IL‐23 driven colitis‐associated colon cancer. Gut. 2016;65(7):1139‐1150. PubMed
