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High-Producer Haplotypes of Tumor Necrosis Factor Alpha and Lymphotoxin Alpha Are Associated With an Increased Risk of Myeloma and Have an Improved Progression-Free Survival After Treatment

From the Department of Haematology, Leeds General Infirmary and University of Leeds; Leukaemia Research Fund Clinical Epidemiology Unit, University of Leeds, Leeds; and Department of Immunology, University of Birmingham, Birmingham, United Kingdom.

Address reprint requests to Gareth Morgan, PhD, Department of Haematology, Algernon Firth Building, University of Leeds, Great George St, Leeds, LS1 3EX United Kingdom; email garethm{at}pathology .leeds.ac.uk.

PURPOSE: To determine the effect of polymorphic variations in the tumor necrosis factor alpha (TNF) and lymphotoxin alpha (LT) genes on the predisposition to myeloma and the effect of these polymorphisms on response to treatment and overall survival.

PATIENTS AND METHODS: Genotype distribution was determined in 63 patients with monoclonal gammopathy of uncertain significance (MGUS) and 198 patients with myeloma and compared with that in 250 age- and sex-matched population-based controls. The effect on treatment response and survival was determined in 171 myeloma patients treated with either conventional or high-dose chemotherapy.

RESULTS: Comparison of the extended TNF/LT haplotype in the myeloma cases and controls showed a significant excess of high-producer alleles in the cases. The double heterozygotes TNF1/2 and LT10.5/5.5 were present in 35.8% of cases but in only 18% of the controls; this presence was associated with a significant increased risk of myeloma (odds ratio, 2.05; 95% confidence interval, 1.26 to 3.35). A similar odds ratio was seen in the MGUS cases, suggesting that this genotype is associated with the initiation of plasma-cell disorders rather than the progression of MGUS to myeloma. The median overall survival time of myeloma patients was 53.8 months and showed no difference with regard to TNF/LT polymorphic status. A trend toward an improved progression-free survival was apparent in cases with a high-producer haplotype, although this effect was seen only in patients receiving high-dose chemotherapy.

CONCLUSION: Individuals with polymorphisms associated with a high production of TNF/LT are at a significantly increased risk of developing MGUS and myeloma. The impact of polymorphic status on overall survival is minimal, although there is a trend toward an increased progression-free survival in the high-producer group.

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