Polymorphism in Cytokine Genes as Prognostic Marker in Hodgkin’s Lymphoma.
Authors: Hohaus Stefan , Giachelia Manuela , Di Febo Annalaura , Martini Maurizio , Massini Giuseppina , Vanata Barbara , Mansueto Giovanna , Guidi Francesco , Larocca Luigi M. , Voso Maria Teresa , Leone Giuseppe 
Published: October 2019

Abstract
It is thought that the production of a variety of cytokines by the malignant Reed-Sternberg cells and the surrounding tissue contributes to the abnormal immune response which is a clinical and pathological feature in Hodgkin’s lymphoma. Single nucleotide polymorphism in the 5′-promoter region of cytokine genes are key factors for cytokine production and may modify the biology of the disease. Recently, differences in the prognosis according to the Interleukin-10 (IL-10) genotype have been shown in patients with diffuse large B cell lymphomas (Lech-Maranda et al, Blood2004; 103:3529). We assessed the distribution of frequencies of polymorphic allele variants in the genes of IL-10 (A-1082G and C-592A), TNF-alpha (C-863A and G-308A) and IL-6 (G-174C) in 218 patients with Hodgkin’s lymphoma and analysed for associations with patient charcteristics and prognosis. The polymorphism were analyzed using a multiplex amplification and mismatched polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique as described by Tseng et al (Tissue Antigens2002; 59:280). DNA was extracted either from peripheral blood or paraffin-embedded lymph node biopsies from 218 patients with Hodgkin’s lymphoma (median age 32 years, range 13–71 years; 104 females and 114 males). 206 patients were treated with standard chemotherapy regimens: 123 patients received ABVD, 33 pts a modified Stanford V regimen (substituting 6 mg/m2 metchloramine with 650 mg/m2 cyclophosphamide), 29 pts MOPP (±ABVD), 21 pts BEACOPP.
The distribution of allele frequencies in Hodgkin’s lymphoma at position -592 of the IL-10 gene was as follows: 43 % were homozygous for the CC genotype, 41 % were heterozygous and 16 % were homozygous for the AA genotype. The IL10 -592AA genotype was associated with a decreased progression-free survival (p=0.0057). The probability of progression-free survival at median time of observation of 4 years for patients homozygous for the IL-10 -592 AA genotype was 33 % (95 % C.I, 14–54 %), while for heterozygous patients and for patients homozygous for the −592 C allele it was 74% (95% C.I., 61–83). When the analysis was restricted to 123 patients treated with ABVD chemotherapy, essentially the same differences in progression-free survival were observed. No associations between genotype distributions of TNF alpha at position −308 and −863, IL-6 at position −174, and IL-10 at position −1082 and clinical variables and prognosis were found. In univariate analysis of established prognostic factors, stage proved to be of prognostic value in our patient group (limited disease in stage I–IIA vs advanced disease in stage IIB–IV, p=0.012) The Cox multivariate analysis showed that IL-10 -592AA genotype and stage were independent prognostic factors (p=0.01 and 0.018, respectively). Our study indicates that the cytokine genotype can predict clinical outcome in patients with Hodgkin’s lymphoma and points to the importance of the genetic background of the host.