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@ARTICLE{Catalano:148815,
author = {C. Catalano$^*$ and M. I. da Silva Filho$^*$ and C.
Frank$^*$ and S. Lu and K. Jiraskova and V. Vymetalkova and
M. Levy and V. Liska and O. Vycital and A. Naccarati and L.
Vodickova and K. Hemminki$^*$ and P. Vodicka and A. N. R.
Weber and A. Försti$^*$},
title = {{E}pistatic effect of {TLR}3 and
c{GAS}-{STING}-{IKK}ε-{TBK}1-{IFN} signaling variants on
colorectal cancer risk.},
journal = {Cancer medicine},
volume = {9},
number = {4},
issn = {2045-7634},
address = {Hoboken, NJ},
publisher = {Wiley},
reportid = {DKFZ-2020-00007},
pages = {1473-1484},
year = {2020},
note = {2020 Feb;9(4):1473-1484#EA:C050#LA:B062#LA:C050#},
abstract = {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.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.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.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.},
cin = {C050 / B062 / HD01},
ddc = {610},
cid = {I:(DE-He78)C050-20160331 / I:(DE-He78)B062-20160331 /
I:(DE-He78)HD01-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31869529},
doi = {10.1002/cam4.2804},
url = {https://inrepo02.dkfz.de/record/148815},
}