A total of 855 NHL cases and 1,206 controls were available for the replication study. The TNFRSF5 −1TT genotype was positively associated with risk of NHL (OR = 1.6, p value for linear trend = 0.001; ). Risk was increased for diffuse large B-cell lymphoma (DLBCL; OR = 2.1, p value for linear trend = 0.001) and FL (OR = 1.9, p value for linear trend = 0.04; ), but not for chronic lymphocytic leukemia (OR = 0.78, p value for linear trend = 0.84).
Table 1 Odds ratios (OR) and 95% confidence intervals (CI) for risk of non-Hodgkin lymphoma (NHL) and NHL by histologic subtype groups associated with the single nucleotide polymorphism (SNP) at position −1 of the Kozak consensus sequence of CD40 gene (more ...)
In the pooled study population of 2,617 NHL cases and 3,605 controls, carriers of the TNFRSF5 −1TT genotype showed a 1.4-fold increase in risk of NHL (p for trend = 0.00009). The excess risk was seen for DLBCL and FL, where the −1TT genotype conferred a 1.6-fold increase in risk (p value for linear trend = 0.002 and 0.001, respectively; ). Risk for chronic lymphocytic leukemia was not increased in association with the −1TT genotype. Study-specific and pooled-adjusted risk estimates and 95% confidence intervals from fixed-effect models for TNFRSF5 −1C>T for all NHL, DLBCL and FL are depicted in . In sensitivity analyses, none of the study altered the observed OR estimate by >10% (). Results from a sensitivity analysis excluding hospital controls were similar to results from the analysis including hospital controls (risk for NHL per allele, OR = 1.15, 95% CI = 1.04–1.26; OR = 1.18, 95% CI = 1.08–1.27; respectively).
Figure 1 Odds ratios (ORs) and 95% confidence intervals (CIs) for risk per allele for the rs13883832 polymorphism associated with risk of all non-Hodgkin lymphoma (NHL), diffuse large B-cell (DLBCL) and follicular lymphoma (FL) obtained from age- and sex-adjusted (more ...)
Skibola et al.5
recently showed that healthy controls and lymphoma cases with the TNFRSF5
−1TT genotype had lower circulating soluble CD40 levels and reduced cell surface expression of CD40 on dendritic cells. This is consistent with previous studies that have reported lower CD40 expression in B cells of −1T versus −1C carriers in B-cell lines derived from patients with Grave’s disease and in transfected Rat-2 fibroblasts.6,11,12
Mice and humans that lack TNFRSF5
gene expression have reduced antibody production and Ig class switching and are unable to mount effective responses against infectious agents.13
Interestingly, the TNFRSF5
−1TT genotype was associated with an elevated risk of the two major NHL subtypes, DLBCL and FL, neoplasms that develop mainly in the germinal center (GC). CD40-CD154 ligation plays a pivotal role in centrocyte differentiation in the GC by downregulation of BCL6.14
Low BCL6 activity permits differentiation of centrocytes into plasma cells or memory cells, allowing B cells to exit the GC. This process may be attenuated by the TNFRSF5
−1TT genotype where low CD40 expression could hinder B- and T-cell interactions, allowing B cells to linger in GCs and undergo further somatic hypermutation and proliferation. This may increase the likelihood of B cells with preneoplastic lesions to progress to malignancy.
The strength of our study is its large sample size that allows the investigation of the main effects of TNFRSF5 −1C>T in relation to the risk of major NHL subtypes. However, small numbers limited the analysis of rarer lymphoma subtypes and subgroups stratified by age and sex.
In conclusion, this pooled analysis highlights the important role of the functional TNFRSF5 −1C>T variant in the etiology of DLBCL and FL. Future studies with careful molecular characterization of GC lymphomas are needed to assess risk related to BCL6 and BCL2 mutation status and further clarify mechanisms that contribute to lymphomagenesis.