title: Cytokine gene polymorphisms and progression-free survival in classical Hodgkin lymphoma by EBV status: results from two independent cohorts.
abstract: BACKGROUND
  Cytokines are important immune mediators of classical Hodgkin lymphoma (CHL) pathogenesis, and circulating levels at diagnosis may help predict prognosis. Germline single nucleotide polymorphisms (SNPs) in immune genes have been correlated with cytokine production and function.
  
  
  METHODS
  We investigated whether selected germline SNPs in IL10 (rs1800890, rs1800896, rs1800871, rs1800872), TNFA (rs1800629), IL6 (rs1800795), ILRN (rs419598), INFG (rs2430561) and CCL17 (rs223828) were associated with circulating levels of related cytokines at diagnosis and progression-free survival (PFS) in CHL. Patients were from France (GELA, N=464; median age=32years) and the United States (Iowa/Mayo Specialized Program Of Research Excellence [SPORE], N=239; median age=38years); 22% of 346 CHL cases with EBV tumor status were positive.
  
  
  RESULTS
  There was no association with any of the SNPs with cytokine levels. Overall, there was no association of any of the SNPs with PFS. In exploratory analyses by EBV status, TNFA rs1800629 (HRAA/AG=2.41; 95%CI, 1.17-4.94) was associated with PFS in EBV-negative GELA patients, with similar trends in the SPORE patients (HRAA/AG=1.63; 95%CI, 0.61-4.40). In a meta-analysis of the two studies, TNFA (HRAA/AG=2.11; 95%CI, 1.18-3.77; P=0.01) was statistically significant, and further adjustment for the international prognostic system did not alter this result.
  
  
  CONCLUSIONS
  This study showed that germline variation in TNFA was associated with CHL prognosis for EBV-negative patients, which will require confirmation. These results support broader studies on the differential impact of genetic variation in immune genes on EBV-positive vs. EBV-negative CHL pathogenesis.
authors.affiliation: Onco-Hematology, Centre Léon Bérard, UMR CNRS 5239, Université Lyon 1, Lyon, France; Health Sciences Research, Mayo Clinic, Rochester, MN, USA. Electronic address: herve.ghesquieres@lyon.unicancer.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Ghesquières
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Beth R
authors.initials: BR
authors.lastname: Larrabee
authors.forename: Eva
authors.initials: E
authors.lastname: Lech-Maranda
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Borrel
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Pauline
authors.initials: P
authors.lastname: Brice
authors.forename: Cristine
authors.initials: C
authors.lastname: Allmer
authors.forename: Annie
authors.initials: A
authors.lastname: Brion
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ziesmer
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gaillard
authors.forename: Brian K
authors.initials: BK
authors.lastname: Link
authors.forename: Aspasia
authors.initials: A
authors.lastname: Stamatoullas
authors.forename: Christophe
authors.initials: C
authors.lastname: Fermé
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.forename: William R
authors.initials: WR
authors.lastname: Macon
authors.forename: Josée
authors.initials: J
authors.lastname: Audouin
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006689:Hodgkin Disease / Q000097:blood / Q000235:genetics* / Q000628:therapy / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D016207:Cytokines
keywords: Cytokines; EBV; Hodgkin lymphoma; Polymorphism; TNFA