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

Research output: Contribution to journalArticle

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. 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.

Details

Authors
  • Calogerina Catalano
  • Miguel Inacio da Silva Filho
  • Christoph Frank
  • Katerina Jiraskova
  • Veronika Vymetalkova
  • Miroslav Levy
  • Vaclav Liska
  • Ondrej Vycital
  • Alessio Naccarati
  • Ludmila Vodickova
  • Kari Hemminki
  • Pavel Vodicka
  • Alexander N.R. Weber
  • Asta Försti
Organisations
External organisations
  • German Cancer Research Centre
  • Charles University in Prague
  • University of Tübingen
  • Institute of Experimental Medicine, Czech Academy of Science
  • Thomayer Hospital
  • Italian Institute for Genomic Medicine (IIGM)
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Article numbere0192385
JournalPLoS ONE
Volume13
Issue number2
Publication statusPublished - 2018 Feb 1
Publication categoryResearch
Peer-reviewedYes