SNP-SNP Interaction in Genes Encoding PD-1/PD-L1 Axis as a Potential Risk Factor for Clear Cell Renal Cell Carcinoma.

Marta Wagner,Agnieszka Halon,Monika Jasek,Pawel Karpinski,Anna Tomkiewicz,Krzysztof Tupikowski,Lidia Karabon,Agata Witkowicz,Kuba Ptaszkowski,Romuald Zdrojowy

doi:10.3390/cancers12123521

Abstract

Simple SummaryImmune checkpoints are key receptors that regulate the immune system and prevent its overactivation. This regulatory mechanism, which under normal conditions is responsible for maintaining immune homeostasis, can be misused by cancer cells, allowing them to avoid recognition and destruction. PD-1 is one of the major immune checkpoints that when interacting with its ligands—PD-L1/PD-L2, regulates the immune surveillance in the tumor microenvironment. We therefore hypothesized that single nucleotide polymorphisms (SNPs) (located in regulatory regions involved in regulation of expression and alternative splicing as well as SNPs introducing changes to the protein sequence) in genes encoding PD-1 and PD-L1 molecules may be associated with the development and outcome of renal cell carcinoma (RCC). We genotyped nine SNPs in PD-1/PD-L1 axis genes, with application of TaqMan allelic discrimination assays, and found that two of them taken together (rs10815225xrs7421861) may be considered to be potential risk factor for clear cell RCC.PD-1/PD-L1 axis plays an important role in maintaining homeostasis and prevention from autoimmunity; however, in the tumor microenvironment, PD-1/PD-L1 interaction is responsible for the evasion of immune surveillance by tumor cells. We therefore hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding PD-1 and PD-L1 molecules are associated with the development and outcome of renal cell carcinoma (RCC). Here we genotyped nine polymorphisms: five of PDCD1: rs36084323G>A, rs11568821G>A, rs2227981C>T, rs10204525G>A, rs7421861T>C and four of PD-L1: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C in 237 RCC patients (including 208 with clear cell RCC (ccRCC)) and 256 controls, with application of allelic discrimination method with use of TaqMan Assays. Interestingly, we found the SNP-SNP interaction between rs10815225 and rs7421861 polymorphisms associated with ccRCC risk. The rs7421861 TC genotype decreased the risk of ccRCC development compared to TT and CC genotypes in the group of rs10815225 GC + CC individuals (OR = 0.21, CI95% = 0.08; 0.54). While possessing of rs10815225 GC or CC genotype increased susceptibility to ccRCC when compared to rs10815225 GG genotype in individuals with rs7421861 TT or CC genotype (OR = 2.40, CI95% = 1.25; 4.61). In conclusion, genetic variants in PDCD1 and PD-L1 genes, especially taken together as SNP-SNP interactions, can be considered to be ccRCC risk factors.

Highlights

In 2000, Hanahan and Weinberg [1] established six hallmarks of cancer which include sustaining proliferative signaling, limitless replication potential, decreased sensitivity to antigrowth signals, evasion of apoptosis, activating invasion and metastasis, and promotion of angiogenesis
We investigated nine polymorphisms—five of which were located in PDCD1 gene: rs36084323G>A (PD-1.1), rs11568821G>A (PD-1.3), rs2227981C>T
The results of our study suggest that polymorphisms of Programmed death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis genes may be associated with the risk of ccRCC development

Summary

Introduction

In 2000, Hanahan and Weinberg [1] established six hallmarks of cancer which include sustaining proliferative signaling, limitless replication potential, decreased sensitivity to antigrowth signals, evasion of apoptosis, activating invasion and metastasis, and promotion of angiogenesis. In 2011 the authors added two additional features which promote tumor development: reprogramming of energetic metabolism and second very important process—evasion from immune surveillance [2]. One of them is development of an immunosuppressive tumor environment through expression of immune checkpoint molecules (ICs), such as CTLA-4, PD-1 and PD-L1, which negatively regulate immune response [3]. Programmed death receptor-1 (PD-1) is a member of CD28 family, expressed on double negative αβ and γδ T cells in thymus and activated T and B cells [4,5]. PD-1 molecule after interaction with its ligands—programmed cell death ligand-1 (PD-L1) and/or programmed cell death ligand-2 (PD-L2), limits some of the T cell functions, including T cell proliferation, apoptosis and IFN-γ production [6]

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