Advanced

Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer

Catalano, Calogerina; da Silva Filho, Miguel Inacio LU ; Frank, Christoph LU ; Jiraskova, Katerina; Vymetalkova, Veronika; Levy, Miroslav; Liska, Vaclav; Vycital, Ondrej; Naccarati, Alessio and Vodickova, Ludmila, et al. (2018) In PLoS ONE 13(2).
Abstract

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.... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
13
issue
2
publisher
Public Library of Science
external identifiers
  • scopus:85041646996
ISSN
1932-6203
DOI
10.1371/journal.pone.0192385
language
English
LU publication?
yes
id
1d67008b-83c8-4fb2-bf4c-d7ebd206ac57
date added to LUP
2018-02-21 11:12:47
date last changed
2018-05-29 09:24:22
@article{1d67008b-83c8-4fb2-bf4c-d7ebd206ac57,
  abstract     = {<p>Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8<sup>+</sup> T cell response through stimulation of NLRC5 expression. Primed CD8<sup>+</sup> 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&gt;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*&lt;0.10. Furthermore, the interaction IFNGR2 rs1059293 C&gt;T—NLRC5 rs289747 G&gt;A (P&lt;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.</p>},
  articleno    = {e0192385},
  author       = {Catalano, Calogerina and da Silva Filho, Miguel Inacio and Frank, Christoph 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         = {1932-6203},
  language     = {eng},
  month        = {02},
  number       = {2},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer},
  url          = {http://dx.doi.org/10.1371/journal.pone.0192385},
  volume       = {13},
  year         = {2018},
}