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

Abstract

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.

Severe Immune-Related Adverse Events in Patients Treated with Nivolumab for Metastatic Renal Cell Carcinoma Are Associated with PDCD1 Polymorphism

“…In this study, we analyzed the potential of three PD-1 SNPs as a predictive biomarker of nivolumab therapeutic outcome in patients with mRCC, because PD-1 is the primary target of this anti-PD-1 antibody [ 29 ]. PD-1, which is broadly expressed in multiple cell types, including T cells, B cells, dendritic cells, and macrophages, plays a role in down-regulating T-cell responses, leading to immune suppression.…”

Silver nanoparticles as proapoptotic drugs: pharmacological basis in non-metastatic skin melanoma

“…13 In this sense, numerous studies have demonstrated the role of specific genes in the development of different types of cancer. [14][15][16][17][18][19] The genetic atlas of cancer is a priority for cell and molecular biology with a view to discovering the different signaling pathways involved, and identifying new targets for the development of antitumor diagnostics and drugs.…”

Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells

“…Similarly, PD-1 rs11568821 synergy with CTLA-4 49AG:CT60 A:A haplotype has been associated with an increased risk of primary biliary cancer (PBC)[ 146 ]. Interactions between PD-L1 rs10815225 and PD-1 rs7421861 polymorphisms were also associated with the development and outcome of ccRCC[ 147 ]. No such observation has been reported so far for HCC, although the interaction between PD-L1 rs4143815 and PD-1 rs11568821 variants was found to be important in the liver transplantation setting.…”