Abstract
BackgroundMalignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment.MethodsWe investigated 50 inflammatory response gene polymorphisms in 355 B-cell non-Hodgkin’s lymphoma (B-NHL) samples encompassing 216 diffuse large B cell lymphoma (DLBCL) and 139 follicular lymphoma (FL) and 307 controls. The effect of single genes and haplotypes were investigated and gene-expression analysis was applied for selected genes. Since interaction between risk genes can have a large impact on phenotype, two-way gene-gene interaction analysis was included.ResultsWe found inherited SNPs in genes critical for inflammatory pathways; TLR9, IL4, TAP2, IL2RA, FCGR2A, TNFA, IL10RB, GALNT12, IL12A and IL1B were significantly associated with disease risk and SELE, IL1RN, TNFA, TAP2, MBL2, IL5, CX3CR1, CHI3L1 and IL12A were, associated with overall survival (OS) in specific diagnostic entities of B-NHL. We discovered noteworthy interactions between DLBCL risk alleles on IL10 and IL4RA and FL risk alleles on IL4RA and IL4. In relation to OS, a highly significant interaction was observed in DLBCL for IL4RA (rs1805010) * IL10 (rs1800890) (HR = 0.11 (0.02–0.50)). Finally, we explored the expression of risk genes from the gene-gene interaction analysis in normal B-cell subtypes showing a different expression of IL4RA, IL10, IL10RB genes supporting a pathogenetic effect of these interactions in the germinal center.ConclusionsThe present findings support the importance of inflammatory genes in B-cell lymphomas. We found association between polymorphic sites in inflammatory response genes and risk as well as outcome in B-NHL and suggest an effect of gene-gene interactions during the stepwise oncogenesis.
Highlights
Normal B-lymphocyte homeostasis requires survival and proliferation signals provided by cells in the lymph node microenvironment
We found inherited single nucleotide polymorphisms (SNPs) in genes critical for inflammatory pathways; TLR9, IL4, TAP2, IL2RA, FCGR2A, TNFA, IL10RB, GALNT12, IL12A and IL1B were significantly associated with disease risk and SELE, IL1RN, TNFA, TAP2, MBL2, IL5, CX3CR1, CHI3L1 and IL12A were, associated with overall survival (OS) in specific diagnostic entities of B-cell non-Hodgkin’s lymphoma (B-NHL)
We explored the expression of risk genes from the gene-gene interaction analysis in normal Bcell subtypes showing a different expression of IL4RA, IL10, IL10RB genes supporting a pathogenetic effect of these interactions in the germinal center
Summary
Normal B-lymphocyte homeostasis requires survival and proliferation signals provided by cells in the lymph node microenvironment. In the case of B-cell non-Hodgkin’s lymphoma (B-NHL) the malignant cells share some similarities with their normal B-cell counterpart linking the immunological inflammatory response to the growth potential of the malignant clone [1,2,3]. Functional single nucleotide polymorphisms (SNPs) affect the inflammatory microenvironment nesting malignant tumours [8]; SNPs may provide a direct effect on the malignant B-cells in the process of tumorigenesis [9]. That the biological effect of such interacting inflammatory response genes with germ line polymorphisms is of pathogenetic impact supported by the investigation of “risk genes” expression in normal B-cell compartments and lymphoma tissue [31,32]. Malignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
