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Immune alteration is the major risk factor for non-Hodgkin lymphoma (NHL), but the specific immune mechanisms remain unresolved. Immune responses depend on environmental/infectious agents which elicit immunologic memory and inherited immune genes, which are highly polymorphic. Two immune gene polymorphisms (TNF G308A and IL10 T3575A) hypothesized to result in increased TNFα levels and promote a Th1/proinflammatory immune response recently were demonstrated to increase NHL risk. To clarify the mechanisms involved in lymphomagenesis from environmental risk factors associated with NHL, we evaluated the effects of suspected environmental risk factors in the presence or absence of a hypothesized proinflammatory milieu conferred by the TNF G308A or IL10 T3575A genotypes. Using data from 1,172 NHL cases and 982 population-based controls from a U.S. multi-center study, we calculated odds ratios (OR) and 95% confidence intervals (CI) for all NHL combined and the two most common NHL subtypes (diffuse large B-cell (DLBCL) (n=371) and follicular lymphoma (n=280)). We found that the recognized risk of NHL associated with autoimmune conditions was apparent only among those with the TNF G308A variant allele (GA or AA genotype) (OR=1.7, 95% CI=0.9-3.4) or IL10 T3575A variant allele (TA or AA genotype) (OR=1.5, 95% CI=0.9-2.4). These results were consistent for both DLBCL and follicular lymphoma. We also found that elevated DLBCL risk associated with being last-born was present only among those with TNF G308A GA/AA genotypes (ORNHL=1.9, 95% CI=1.0-3.6; ORDLBCL=2.5, 95% CI=1.1-6.0) or IL10 T3575A TA/AA genotypes (ORNHL=1.7, 95% CI=1.1-2.5; ORDLBCL=2.7, 95% CI=1.6-4.8). No effect was seen for follicular lymphoma, regardless of genotype. Similarly, elevated DLBCL risk associated with obesity (body mass index of 35+ versus <25 kg/m2) was observed only among those with TNF G308A GA/AA genotypes (ORDLBCL=2.5, 95% CI=1.1-5.7) or IL10 T3575A TA/AA genotypes (ORDLBCL=2.0, 95% CI=1.1-3.5). Again, no effect was seen for follicular lymphoma. These results require replication but may reflect that autoimmune conditions, late birth order, and obesity act through a common inflammatory pathway and that individuals with variant TNF and IL10 genotypes are most susceptible to lymphomagenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA