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Investigation of si...
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Catalano, CalogerinaGerman Cancer Research Centre
(author)
Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer
- Article/chapterEnglish2018
Publisher, publication year, extent ...
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2018-02-06
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Public Library of Science (PLoS),2018
Numbers
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LIBRIS-ID:oai:lup.lub.lu.se:1d67008b-83c8-4fb2-bf4c-d7ebd206ac57
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https://lup.lub.lu.se/record/1d67008b-83c8-4fb2-bf4c-d7ebd206ac57URI
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https://doi.org/10.1371/journal.pone.0192385DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on CRC risk in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G (OR: 1.60, 95% CI: 1.13–2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51–0.96, dominant model). Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of CRC, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2 variants, to evaluate their involvement in the risk of CRC development. Overall we obtained 18 pairwise interactions within and between the NLRC5 ad PD-L1 genes and 6 more when IFNGR variants were added. Thirteen out of the 24 interactions were below the threshold for the FDR calculated and controlled at an arbitrary level q*<0.10. Furthermore, the interaction IFNGR2 rs1059293 C>T—NLRC5 rs289747 G>A (P<0.0001) remained statistically significant even after Bonferroni correction. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also PD-1-based immunotherapy in CRC.
Subject headings and genre
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da Silva Filho, Miguel InacioGerman Cancer Research Centre(Swepub:lu)med-md_
(author)
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Frank, ChristophGerman Cancer Research Centre(Swepub:lu)med-cfr
(author)
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Jiraskova, KaterinaInstitute of Experimental Medicine, Czech Academy of Science,Charles University in Prague
(author)
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Vymetalkova, VeronikaInstitute of Experimental Medicine, Czech Academy of Science,Charles University in Prague
(author)
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Levy, MiroslavCharles University in Prague,Thomayer Hospital
(author)
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Liska, VaclavCharles University in Prague,Thomayer Hospital
(author)
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Vycital, OndrejThomayer Hospital,Charles University in Prague
(author)
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Naccarati, AlessioItalian Institute for Genomic Medicine (IIGM),Institute of Experimental Medicine, Czech Academy of Science
(author)
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Vodickova, LudmilaInstitute of Experimental Medicine, Czech Academy of Science,Charles University in Prague
(author)
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Hemminki, KariLund University,Lunds universitet,Allmänmedicin och klinisk epidemiologi,Forskargrupper vid Lunds universitet,Family Medicine and Clinical Epidemiology,Lund University Research Groups,German Cancer Research Centre(Swepub:lu)med-khk
(author)
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Vodicka, PavelCharles University in Prague,Institute of Experimental Medicine, Czech Academy of Science
(author)
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Weber, Alexander N.R.University of Tübingen
(author)
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Försti, AstaLund University,Lunds universitet,Allmänmedicin och klinisk epidemiologi,Forskargrupper vid Lunds universitet,Family Medicine and Clinical Epidemiology,Lund University Research Groups,German Cancer Research Centre(Swepub:lu)med-asf
(author)
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German Cancer Research CentreInstitute of Experimental Medicine, Czech Academy of Science
(creator_code:org_t)
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In:PLoS ONE: Public Library of Science (PLoS)13:21932-6203
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