Tumor Necrosis Factor Alfa (TNFα), Lymphotoxin Alfa (Ltα) and Interleukin-6 (IL-6) Polymorphisms in Brazilian Multiple Myeloma (MM) Patients.
Authors: Duch Cibele R. , Figueiredo Maria S. , Almeida Manuella S.S. , Ribas Christian , Colleoni Gisele W.B. , Bordin José O. 
Published: April 2020

Abstract
Background: MM is a plasma cell neoplasm of unknown etiology. Recent studies have shown that cytokines play an important stimulatory or inhibitory role in myeloma cell growth. IL-6 is an essential growth factor for MM and increased IL-6 serum levels have been correlated with poor prognosis. TNFα and LTα are two critical cytokines produced early in the inflammatory reaction process and potent inducers of IL-6 that may, indirectly, stimulate plasma-cell growth. Considering that the serum level of cytokines also depends on genetic control, polymorphisms in promoter regions of these genes may play a role in MM pathogenesis.
Aims: 1) to determine the prevalence of IL-6, TNFα and LTα genotypes in MM patients and controls; 2) to verify the impact of these genoypes on patients’ survival.
Methods: Sixty healthy individuals (matched by age, sex, and race) and fifty-two MM patients, enrolled from a sole institution from November 2002 to November 2003 were studied. Relevant clinical and laboratory characteristics documented at diagnosis were evaluated. Molecular analyses were made by polymerase chain reaction (PCR) followed by specific endonuclease restriction disgestion to determine the following polymorphisms: IL-6 (−174 G/C), TNFα (−308 G/A, named T1 and T2 respectively) and LTα (+252 G/A, named 10.5 and 5.5 respectively). Event free survival (EFS) and overall survival (OS) were analyzed by Kaplan-Meier curves.
Results: IL-6, TNFα and LTα genotypes are presented in the table. We found no difference in the prevalence of IL-6, TNFα and LTα genotypes when MM patients were compared to control group. Similarly, when TNFα and LTα were analyzed as haplotype, no difference was observed in both groups. Median EFS and OS was analyzed for each cytokine. The median EFS for the GG genotype of IL-6 was 17 months compared to 13 months for the CG or CC genotypes (p=0.09). The median EFS for the presence of at least one T2 allele of TNFα was 26 months compared to 13 months for the homozygous T1 genotype (p=0.06). The median OS for the 10.5/10.5 genotype of the LTα was 112 months compared to 42 months for the 5.5/10.5 or 5.5/5.5 genotypes (p=0.04). We observed tendency to prolonged EFS on the GG genotype of IL-6, and with the presence of at least one T2 allele of TNFα. A longer OS was seen on 10.5/10.5 genotype of the LTα. We concluded that the 10.5/10.5 genotype, related to normal production of LTα, may have influence on OS in our group of patients. We believe that multicenter studies and longer follow up could help us to confirm these results.
GENOTYPE DISTRIBUTION
Genotype patients number frequency (%) control number frequency (%) p ns = not significant IL-6 GG 28/52 53.8 35/60 58.3 ns IL-6 GC 22/52 42.3 23/60 38.3 ns IL-6 CC 2/52 3.8 2/60 3.3 ns TNF α T1/T1 41/52 78.8 45/60 75.0 ns TNF α T1/T2 9/52 17.3 14/60 23.3 ns TNF α T2/T2 2/52 3.8 1/60 1.7 ns LT α 10.5/10.5 26/52 50.0 23/60 38.3 ns LT α 10.5/5.5 18/52 34.6 30/60 50.0 ns LT α 5.5/5.5 8/52 15.4 7/60 11.7 ns