A family history of lymphoma or related hematopoietic neoplasm has been reported to increase the risk of non-Hodgkin lymphoma (NHL) among close relatives of affected individuals. Postulating that genetic variants in immune and inflammatory response genes could affect the risk of developing NHL, Rothman and colleagues studied single nucleotide polymorphisms in nine genes relevant to lymphoid development. Genotyping was performed for NHL patient (n=3586) and control (n=4018) DNA samples collected from eight North American and European centers participating in the International Lymphoma Epidemiology Consortium (InterLymph). To maximize study population homogeneity, only white individuals, most of European descent, were included. Six laboratories performed the genotyping analyses, and risk estimates were determined by a random-effects logistic regression model. Positive associations were identified for two of the genes analyzed. The tumor necrosis factor polymorphism TNF-308G→A was associated with increased risk of NHL, especially diffuse large B-cell lymphoma (DLBCL). Similarly, the interleukin 10 polymorphism IL10 575T→A was also associated with increased risk of DLBCL but not follicular or other NHL histologies. Risk of DLBCL was doubled (odds ratio 2.13) in those individuals who were homozygous for the TNF polymorphism and who also carried the IL 10 polymorphism.
Epidemiologic studies have shown a two- to four-fold or greater risk of NHL among first-degree and other close relatives of patients with lymphoma, CLL, or related lymphoid malignancy. TNF and IL 10 are immune cytokines involved in the regulation of inflammatory and T cell responses, apoptosis, and lymphoid growth. Rothman and colleagues suggest that polymorphisms which alter cytokine expression levels or function, and perhaps immune and inflammatory responses, could in turn contribute to lymphomagenesis. These results, while showing the power of such a large-scale analysis across multiple epidemiologic data bases, will nonetheless need to be confirmed and extended in additional studies currently underway by the InterLymph Consortium.
Furthermore, parallel studies will need to be pursued for other ethnic groups and for additional subtypes of lymphoma and related neoplasms. The authors’ findings also provide important clues for investigators pursuing the mechanisms of lymphomagenesis and could lead to new insights regarding the interplay of genetic and environmental or infectious etiologies relevant to lymphoma pathogenesis. Such understanding would be an important step in devising screening and prevention approaches for NHL, now the fifth leading type of cancer in the United States.
