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


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 TNFalpha/LTalpha 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 TNFalpha/LTalpha 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.


CONCLUSIONS
Individuals with polymorphisms associated with a high production of TNFalpha/LTalpha 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.
Department of Haematology, Leeds General Infirmary and University of Leeds, UK.
F E
FE
Davies
S J
SJ
Rollinson
A C
AC
Rawstron
E
E
Roman
S
S
Richards
M
M
Drayson
J A
JA
Child
G J
GJ
Morgan
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D016022:Case-Control Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011110:Polymorphism, Genetic; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha