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Epistatic effect of TLR3 and cGAS-STING-IKKε-TBK1-IFN signaling variants on colorectal cancer risk

Catalano, Calogerina ; da Silva Filho, Miguel Inacio LU ; Frank, Christoph LU ; Lu, Shun ; Jiraskova, Katerina ; Vymetalkova, Veronika ; Levy, Miroslav ; Liska, Vaclav ; Vycital, Ondrej and Naccarati, Alessio , et al. (2020) In Cancer Medicine 9(4). p.1473-1484
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CRC, interaction, polygenic-risk-score, risk
in
Cancer Medicine
volume
9
issue
4
pages
12 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:31869529
  • scopus:85076933386
ISSN
2045-7634
DOI
10.1002/cam4.2804
language
English
LU publication?
yes
id
7e68dd73-2289-4598-855a-6e2c29a02dd2
date added to LUP
2020-01-10 15:46:37
date last changed
2023-01-23 22:10:34
@article{7e68dd73-2289-4598-855a-6e2c29a02dd2,
  abstract     = {{<p>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.</p>}},
  author       = {{Catalano, Calogerina and da Silva Filho, Miguel Inacio and Frank, Christoph and Lu, Shun and Jiraskova, Katerina and Vymetalkova, Veronika and Levy, Miroslav and Liska, Vaclav and Vycital, Ondrej and Naccarati, Alessio and Vodickova, Ludmila and Hemminki, Kari and Vodicka, Pavel and Weber, Alexander N.R. and Försti, Asta}},
  issn         = {{2045-7634}},
  keywords     = {{CRC; interaction; polygenic-risk-score; risk}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1473--1484}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Cancer Medicine}},
  title        = {{Epistatic effect of TLR3 and cGAS-STING-IKKε-TBK1-IFN signaling variants on colorectal cancer risk}},
  url          = {{http://dx.doi.org/10.1002/cam4.2804}},
  doi          = {{10.1002/cam4.2804}},
  volume       = {{9}},
  year         = {{2020}},
}