Abstract
Background: Non-Hodgkin Lymphoma (NHL) belong to the seventh most common cancer in Europe and constitute the tenth most commonly diagnosed cancer worldwide. Apart from risk factors such as certain infectious agents and immunodeficiency syndromes, genetic variants related to immunity have been associated with lymphomagenesis. Previous studies suggested an important role of the JAK-STAT signalling pathway in tumour development. Therefore, we explored genetic variants in the JAK-STAT pathway associated with lymphoma risk. Material and Methods: In total, 1481 lymphoma cases and 1491 age, sex and study centre matched controls of the EpiLymph study, a multi-centre case-control study on the aetiology of lymphomas among adults in Europe, were genotyped for 1536 single nucleotide polymorphisms (SNPs) using GoldenGate BeadArrayTM Technology (Illumina, San Diego, CA). Association between SNPs and haplotypes of the JAK-STAT pathway and risk of Hodgkin lymphoma (HL), NHL and most frequent NHL subtypes were estimated by calculating Odds Ratios (OR), the corresponding 95% confidence intervals (CI) and p-values using unconditional logistic regression (SAS 9.2). Results: Among 220 relevant SNPs, polymorphisms in several genes (STAT3, STAT6, IFNG, BMF, STAT5A) were significantly associated with lymphoma risk. Reduced risk for NHL overall and diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were seen in association with seven STAT3 SNPs in high linkage disequilibrium and respective haplotypes. Variant rs4103200 conferred an about 20% reduced NHL risk (ORCG 0.79, 95% CI 0.66–0.94, ORGG of 0.78, 95% CI 0.66–0.91, ptrend=0.002). For DLBCL and FL a reduced risk with rs4103200 was also evident. A putatively functional variant in STAT6 previously associated with IgE levels (rs324011) was inversely associated with HL risk (ORTC/CC: 0.61, 95% CI 0.45–0.82, p=0.001). Conclusion: Our results implicate a relevant role of the JAK-STAT signalling in the development of lymphoma. Furthermore, our data support previously found associations between genetic variants of STAT genes and immune phenotypes.
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