Association Between Genetic Variants Within TNF And IL-10 Genes And Clinical Characteristics In Childhood Malignant Lymphoma

Objective To estimate the association of genetic variation within the tumor necrosis factor (TNF-α-308 G/A, rs1800629), lymphotoxin-a (LTα+252 A/G, rs909253), interleukin-10 (IL-10-1082 G/A, rs1800896) genes with clinical characteristics and prognosis in childhood malignant lymphoma.Subjects and Mothods Subjects:Malignant lymphoma patients diagnosed in Children’s Hospital of Fudan University, Shanghai from July 2004 to July 2011 were included in our study. Methods:DNA was extracted from peripheral blood and genotyped using SNaPshot method. Association of the genetic variants with clinical characteristics (age, sex, type of lymphoma, stage at diagnosis, outcome) were analyzed using x2 test. Probability of event-free survival was performed according to Kaplan and Meier, with differences compared by the log-rank test.Results Of the total 62 pediatric patients (17 female,45 male) enrolled in the study, 6 abandoned treatment after diagnosed,2 patients were lost to follow up. The average age at diagnose is 7.93 years, ranges from 12 months to 14 y 7 m.51 patients were diagnosed as non-Hodgkin lymphoma (15 female,36 male, average age at diagnose: 7.25 y),11 were diagnosed a Hodgkin disease (1 female,10 male, average age at diagnose:8.22 y). TNF-α-308 and LTα+252 was in linkage disequilibrium, TNF1 is associated with LTa 10.5 (x2=8.0756,P=0.0045), TNF2 is associated with LTa 5.5 (x2=4.0678, P=0.045). We defined the carrier state of≥2 TNF2 or LTa 5.5 genotype as TNF high-risk, carrier state of<2 TNF2 or LTα5.5 genotype as TNF low-risk. We didn’t find the difference of TNF carrier state in age, sex, type of lymphoma, stage at diagnosis and treatment outcome (P>0.05). In our probability of event-free survival analysis (average follow-up time 31.9 months, ranges from 1 to 87 months), the median survival time in TNF high-risk group is 34 months, most cases of low-risk group’s survival rate are longer than 0.5. The 5 year disease free survival rate is 46.8% for TNF high-risk, which was significantly different from TNF low-risk group(75.0%) (Log-rank test, P=0.045). The 5 year disease free survival rate for non-Hodgkin lymphoma in TNF high-risk and TNF low-risk group is 53.5% and 71.4% respectively (Log-rank test, P=0.288). We were not able to observe the difference of IL-10-1082 genotype frequencies in age, sex, type of lymphoma, stage at diagnosis and treatment outcome (P>0.05). However, there is more AA genotype in III, IV stage of Hodgkin disease compared to I, II stage. The 5 year disease free survival rate is 66.7% and 75.9% for IL-10-1082 AG and IL-10-1082 AA group respectively (Log-rank test, P=0.963). The 5 year disease free survival rate for non-Hodgkin lymphoma in IL-10-1082 AG and IL-10-1082 AA group is 60% and 77.3% respectively (Log-rank test, P=0.809).Conclusions The carrier state of combined TNF-α-308 and LTα+252 allele is associated with prognosis of malignant lymphoma in childhood, it could be used as a marker in the estimation of prognosis in pediatric lymphoma. We didn’t find the association between IL-10-1082 and prognosis of childhood malignant lymphoma.