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Infectious agents and immune dysfunction are known risk factors of lymphoid neoplasms. Proteins at the interphase between environment and immune system may have an important mediating role in lymphomagenesis. Toll-like receptors (TLR) belong to a group of pattern recognition receptors with importance for innate immune response and inflammatory processes. Single nucleotide polymorphisms in these genes have been implicated in a number of infectious, inflammatory and neoplastic diseases.

The objective of this study was to estimate the risk of lymphoma and specific subtypes associated with genetic variants in TLR genes in the European multi-center case-control study Epilymph. The study comprised newly diagnosed cases with a lymphoid malignancy recruited between 1998 and 2004 in 6 European countries (Czech Republic, France, Germany, Ireland, Italy, and Spain). Lymphomas were diagnosed and classified following the criteria of the WHO Classification for Neoplastic Diseases of the Lymphoid Tissues. Controls were population-based or hospitalized patients matched to the cases by 5-year age group, gender and study center. Informed consent was obtained from all subjects. Interviews were conducted to collect data on demographics, medical and family history as well as environmental exposures. Genomic DNA of 1890 cases and 1918 controls were genotyped for polymorphisms with putative functional relevance in TLR1 (-7202A>G), TLR2 (Arg753Gln, -16933T>A), TLR4 (Asp299Gly), TLR5 (Arg392Stop), and TLR9 (-1237T>C, -14486T>C) using PyrosequencingTM-technology. Odds Ratios (OR) and 95% confidence intervals (CI) for the association of the variants with the risk of lymphoma overall and individual subtypes were calculated using unconditional logistic regression analysis.

None of the variants in TLR genes was associated with overall lymphoma risk. However, we found some TLR gene polymorphisms associated with subtypes of lymphoma, especially with chronic lymphocytic leukemia (CLL, n=329), marginal zone lymphoma (MZL, n=113), and T-cell NHL (T-NHL, n=102). A 30% decreased risk for CLL (OR=0.72, 95%CI=0.55-0.95) was seen in association with the TLR2 -16933T>A variant. The TLR9 -1486T>C variant conferred an increased risk of T-NHL (CC versus TT: OR=2.35, 95%CI=1.35-4.10) and follicular lymphoma (TC/CC versus TT: OR=1.4, 95%CI=1.00-1.94). Homozygosity of the TLR5 Arg392Stop codon variant was associated with a 4.4-fold risk of CLL (95%CI=1.09-17.4) and an 8.3-fold risk of MZL (95%CI=1.54-44.8). The combined occurrence of the TLR9 -1237T>C variant and homozygosity for either the TLR5 392Stop codon or the TLR4 299Gly variant was associated with a 9.3-fold increased risk of MZL (95%CI=2.67-32.25).

These results suggest a role of putative functional TLR gene variants in the etiology of some lymphoma subtypes. It will be interesting to explore theses findings further in conjunction with biomarkers of infectious agents implicated in lymphomagenesis.

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