title: Inherited Inflammatory Response Genes Are Associated with B-Cell Non-Hodgkin's Lymphoma Risk and Survival.
abstract: BACKGROUND
  Malignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Kaspar René
authors.initials: KR
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Rudi
authors.initials: R
authors.lastname: Steffensen
authors.affiliation: Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Mette Dahl
authors.initials: MD
authors.lastname: Bendtsen
authors.affiliation: Department of Haematology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodrigo-Domingo
authors.affiliation: Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: John
authors.initials: J
authors.lastname: Baech
authors.affiliation: Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Thure Mors
authors.initials: TM
authors.lastname: Haunstrup
authors.affiliation: Department of Haematology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Kim Steve
authors.initials: KS
authors.lastname: Bergkvist
authors.affiliation: Department of Haematology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmitz
authors.affiliation: Department of Haematology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Julie Stoeveve
authors.initials: JS
authors.lastname: Boedker
authors.affiliation: Department of Haematopathology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Preben
authors.initials: P
authors.lastname: Johansen
authors.affiliation: Department of Haematology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkaeær
authors.affiliation: Department of Haematology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Boeøgsted
authors.affiliation: Department of Haematology, Aalborg University Hospital, Aalborg, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Johnsen
mesh_terms: D000368:Aged; D000483:Alleles; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053710:Interleukin-10 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008224:Lymphoma, Follicular / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012306:Risk; D016019:Survival Analysis; D059467:Transcriptome
chemical_list: C081846:IL10RB protein, human; C508598:IL4 protein, human; C504000:IL4R protein, human; D053710:Interleukin-10 Receptor beta Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D016753:Interleukin-10; D015847:Interleukin-4