Inherited Inflammatory Response Genes Are Associated with B-Cell Non-Hodgkin's Lymphoma Risk and Survival

• Published in: PloS one 2015-10, Vol.10 (10), p.e0139329-e0139329
• Main Authors: Nielsen, Kaspar René, Steffensen, Rudi, Bendtsen, Mette Dahl, Rodrigo-Domingo, Maria, Baech, John, Haunstrup, Thure Mors, Bergkvist, Kim Steve, Schmitz, Alexander, Boedker, Julie Stoeveve, Johansen, Preben, Dybkaeær, Karen, Boeøgsted, Martin, Johnsen, Hans Erik
• Format: Article
• Language: English
• Subjects: Aged; Alleles; B-cell lymphoma; Blood & organ donations; Cancer; Cell survival; Clinical medicine; CX3CR1 protein; Cytokines; Diagnostic systems; Fc receptors; Female; Gene expression; Gene loci; Genes; Genetic aspects; Genetic diversity; Genomes; Genotype; Growth factors; Haplotypes; Health risks; Hematology; Hospitals; Humans; Immunology; Inflammation; Inflammatory response; Interleukin 1; Interleukin 10; Interleukin 2 receptors; Interleukin 4; Interleukin 5; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukin-10 Receptor beta Subunit - genetics; Interleukin-10 Receptor beta Subunit - metabolism; Interleukin-4 - genetics; Interleukin-4 - metabolism; Interleukin-4 Receptor alpha Subunit - genetics; Interleukin-4 Receptor alpha Subunit - metabolism; Leukemia; Linkage Disequilibrium; Lymphatic system; Lymphocytes B; Lymphoma; Lymphoma, Follicular - etiology; Lymphoma, Follicular - genetics; Lymphoma, Follicular - mortality; Lymphoma, Large B-Cell, Diffuse - etiology; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - mortality; Male; Medical prognosis; Medical research; Medicine; Middle Aged; Non-Hodgkin's lymphomas; Odds Ratio; Phenotypes; Polymorphism, Single Nucleotide; Proportional Hazards Models; Risk; Risk factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Survival; Survival Analysis; TLR9 protein; Toll-like receptors; Transcriptome; Tumor microenvironment; Tumor necrosis factor-α; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139329

Malignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment. We 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. We 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. The 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.