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

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Epistatic effect of TLR3 and cGAS-STING-IKKε-TBK1-IFN signaling variants on colorectal cancer risk.
Cancer Medicine ( IF 2.9 ) Pub Date : 2019-12-23 , DOI: 10.1002/cam4.2804
Calogerina Catalano _{1,

2} , Miguel Inacio da Silva Filho ₁ , Christoph Frank ₁ , Shun Lu ₃ , Katerina Jiraskova _{4,

5} , Veronika Vymetalkova _{4,

5,

6} , Miroslav Levy ₇ , Vaclav Liska _{6,

8} , Ondrej Vycital _{6,

8} , Alessio Naccarati _{4,

9} , Ludmila Vodickova _{4,

5,

6} , Kari Hemminki _{1,

10} , Pavel Vodicka _{4,

5,

6} , Alexander N R Weber ₁₁ , Asta Försti _{1,

10,

12,

13}

Affiliation

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu, China.
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, the Czech Academy of Sciences, Prague, Czech Republic.
1st Medical Faculty, Institute of Biology and Medical Genetics, Charles University, Prague, Czech Republic.
Faculty of Medicine in Pilsen, Biomedical Center, Charles University Prague, Pilsen, Czech Republic.
First Medical Faculty, Department of Surgery, Charles University and Thomayer Hospital, Prague, Czech Republic.
Department of Surgery, Teaching Hospital and Medical School of Charles University, Pilsen, Czech Republic.
Molecular and Genetic Epidemiology, Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Baden-Württemberg, Tübingen, Germany.
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

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.

中文翻译：

TLR3和cGAS-STING-IKKε-TBK1-IFN信号变体对大肠癌风险的上位作用。

目的最近有报道称，由于相关基因表达失控，TLR3 / cGAS-STING-IFN信号转导在大肠癌中受到干扰。我们的研究旨在调查这些基因中潜在调控变异体对1424例CRC患者和1114例健康对照组的捷克人群中散发性结直肠癌（CRC）风险的影响。方法使用各种在线生物信息学工具，例如UCSC浏览器，HaploReg，Regulome DB，Gtex Portal，SIFT，PolyPhen2和miRNA预测工具，选择TLR3，CGAS，TMEM173，IKBKE和TBK1基因中的变异体。结果针对年龄和性别进行了Logistic回归分析，发现CRC风险与以下三种变异之间存在名义关联：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值=。03）和TMEM173 rs13153461（OR：1.53，95％CI：1.03-2.27，P-value = .03）。它们的累积效应表明，与具有0-2个风险等位基因的携带者相比，具有5-6个风险等位基因的携带者的CRC风险增加了三倍。计算这些基因与先前基因型化的IFNAR1，IFNAR2，IFNA，IFNB，IFNK，IFNW，IRF3和IRF7基因之间的上位相互作用，以测试它们对CRC风险的影响。总的来说，我们在CGAS，TMEM173，IKBKE和TBK1基因内部和之间获得了九种成对相互作用。Bonferroni校正后，其中两个仍具有统计学意义。当将IFN变体添加到分析中时，观察到另外的52种相互作用。结论我们的数据表明上位性相互作用和高风险等位基因可能在CRC致癌作用中起重要作用，

更新日期：2019-12-25

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