SNPs in genes encoding for IL-10, TNF-α, and NFκB p105/p50 are associated with clinical prognostic factors for patients with Hodgkin lymphoma

Abstract

Classical Hodgkin lymphoma (cHL) is a B-cell-derived malignant neoplasia that has a unique histological distribution, in which the scarce malignant Hodgkin and Reed-Sternberg cells are surrounded by nonmalignant inflammatory cells. The interactions between the malignant and inflammatory cells are mediated by aberrantly produced cytokines, which play an important role in tumor immunopathogenesis. Single nucleotide polymorphisms (SNPs) in genes encoding cytokines and their regulatory proteins may influence the peripheral levels of these molecules and affect disease’s pathobiology. In this study, we evaluate SNPs in the promoter regions of the genes encoding for two key cytokines in Hodgkin lymphoma: IL-10 (SNP/pIL10–592, rs1800872; and SNP/pIL10–1082, rs1800896) and TNF-α (SNP/pTNF -238, rs361525; and SNP/pTNF -862, rs1800630), as well as an SNP in the intronic region of the NFκB1 gene (SNP/iNFKB1, rs1585215), an important regulator of cytokine gene expression. We then look to their possible association with clinical and laboratory features in cHL patients. Seventy-three patients with cHL are genotyped by qPCR-high resolution melting. The SNPs’ genotypes are analyzed individually for each SNP, and when more than two allelic combinations are identified, the genotypes are also divided into two groups according to proposed biological relevance. By univariate analysis, patients harboring SNP/pTNF -238 AG genotype more frequently have EBV-associated cHL compared to homozygous GG, whereas the presence of mediastinal disease (bulky and nonbulky) is more common in the pIL10–592 AC/CC group compared to the AA homozygous group. Patients with SNP/iNFKB1 AA genotype more frequently have stage IV and extranodal disease at diagnosis. These results indicate that some SNPs’ genotypes for IL-10 and TNF-α genes are associated with prognostic parameters in cHL. For the first time, the SNP/iNFKB1 is described in association with clinical features of the disease.

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“…Similarly, both the transcriptional and translational processes can be intricate in the rule of TNF-α synthesis. At the transcriptional level, nuclear factor kappa B (NFκB) considered the major redox-sensitive transcriptional factor associated with TNF-α production (9).…”

NFkB Pathway and Hodgkin Lymphoma

“…Some SNPs can also be involved in the clinical presentation and aggressiveness of the disease. For instance, a SNP in the intronic region of the NFkappaB1 gene (SNP/iNFKB1, rs1585215), an important regulator of cytokine gene expression, is more frequently associated with stage IV and extranodal disease at diagnosis [ 22 ].…”

The genetic polymorphisms of immune‐related genes contribute to the susceptibility and survival of lymphoma

“…Patients with AA genotype in rs1585215 of NFKB1 in the NF‐κB pathway were more likely to develop Stage IV and extranodal lesions when diagnosed. Besides, AG genotype of TNF‐α was more likely to develop EBV‐related chronic lymphocytic leukemia than homozygous GG 11 . As one of the genes that control the activity of T lymphocytes, protein tyrosine phosphatase nonreceptor 22 (PTPN22) has also been reported to play an important role in the development of many autoimmune diseases in recent years.…”

“…Besides, AG genotype of TNF-α was more likely to develop EBV-related chronic lymphocytic leukemia than homozygous GG. 11 As one of the genes that control the activity of T lymphocytes, protein tyrosine phosphatase nonreceptor 22 (PTPN22) has also been reported to play an important role in the development of many autoimmune diseases in recent years. PTPN22 dephosphorylates NLRP3 inflammatory cells to limit the retention of NLRP3 in autophagy and to degrade it in autolysosomes, 12 and its rs2476601 genotype can down-regulate the TCR signal system and reduce the affinity of Csk and T cells.…”