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 pair-wise 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.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer mortality worldwide [1]
Logistic regression analysis adjusted for age and sex reported an association between rectal cancer risk and 2 Nod-like receptors (NLRs) family (NLRC5) single nucleotide polymorphisms (SNPs), rs1684575 (OR: 1.60, 95% confidence interval (CI): 1.13–2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51–0.96, dominant model) (S2 Table)
In our case-control study comprising up to 1424 cases and 1114 healthy controls, we investigated the role of genetic polymorphisms in the regulatory regions of NLRC5, programmed death-ligand 1 (PD-L1) and the previously genotyped regulatory SNPs in the interferon gamma receptor (IFNGR) genes on the risk of CRC
Summary
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer mortality worldwide [1]. The intestinal tract is continuously exposed to both potential pathogens and beneficial commensal microorganisms; the homeostatic balance between tolerance and immunity represents a regulatory challenge to the mucosal immune system [3]. In this context a pivotal role is played by the epithelial cells that monitor the intestinal microenvironment for pathogenic and commensal microorganisms via so-called pattern recognition receptors (PRRs), e.g. Toll-like receptors (TLRs), and in turn influence the function of antigen presenting cells and lymphocytes [3,4]. Cytokine production and CD8+ T cell expansion is necessary for generating an effective immune defense against invading harmful pathogens [12]
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