The role of genes in the development of non-Hodgkin's lymphomas

An international consortium of epidemilogists - including Dr. Alexandra Nieters and Professor Nikolaus Becker of the Clinical Epidemiology Division of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) - has conducted the first ever investigation of genetic factors in the development of non-Hodgkin’s lymphoma (NHL) in a study called InterLymph.

The researchers collaborating within the International Lymphoma Epidemiology Consortium have found out that variations of individual DNA building blocks in genes encoding for the cellular signaling molecules tumor necrosis factor (TNF) and interleukin 10 (IL-10) increase the risk of developing non-Hodgkin’s lymphoma.

The study is a step towards developing a deeper understanding of the development of lymphomas, which may lead to novel prevention and treatment approaches in the future. The researchers have now published their results online in the journal Lancet Oncology.

The study is based on data gathered in eight case-control studies from different countries involving a total of 3586 NHL patients and 4018 healthy individuals as control group. The epidemiologists focused their attention on 12 different variations of single DNA building blocks, called single nucleotide polymorphisms, which are located in genes whose products regulate important functions in immune response and anti-inflammatory reaction. For two variations concerning the genes for (i) tumor necrosis factor and (ii) interleukin, the investigators found an elevated individual risk of non-Hodgkin’s lymphoma. Analyzing different NHL subtypes, they discovered that the two gene variations specifically increase the risk of diffuse large B-cell lymphoma, the most common type of malignant lymphoma. The disease risk of individuals carrying one copy of the rare polymorphism in the TNF gene is elevated by 29 percent; a second copy increases the risk by 65 percent. A combination of both gene variants in TNF and IL-10 leads to a 100 percent increase of individual risk. The risk of follicular lymphoma, a generally less aggressive type of lymphoma, is not influenced by the combination of these variants.

In recent years, lymphoma research has focused primarily on the search for environmental or lifestyle risk factors. The study now published is an important step towards a deeper understanding also of genetic factors in NHL development. “We have had two hits in twelve factors we investigated. Now the real work starts, because we are planning to study not only the influence of genetic factors on the development of non-Hodgkin’s lymphomas, but also on lymphomas in general. Basically, we are interested here in all genes that influence signaling pathways within the cell such as in inflammatory processes or cellular DNA repair mechanisms,” states Alexandra Nieters, assessing the relevance of the study for lymphoma research. In the future, epidemiologists are planning to put more emphasis on combined investigations of genetic and environmental factors in lymphoma development.

The study underlines the importance of international collaboration in the search for genetic causes of chronic diseases: It only became possible by pooling several studies from different countries. This was the only way to obtain a sufficient number of participants to provide statistically supported effects, which could not have been obtained based on the individual studies.

Established in 2002, the InterLymph Consortium is a collaboration of researchers from the United States, Canada, Australia, Germany, Italy, U.K., France, Spain, Ireland, Czechia, Sweden and Denmark who are jointly searching for possible causes and risk factors of cancers of the lymphatic system. There are plans to extend the collaboration to include Asian and African countries.

Lymphomas are divided into two main types: Hodgkin’s disease and non-Hodgkin’s lymphomas (NHL). Non-Hodgkin’s lymphomas include many variations of lymphatic cancers, which differ strongly in tissue structure and disease progression. In Germany, approximately 13,000 people are diagnosed with NHL each year, more that 5,000 die of it each year.

This project of the Interlymph Consortium is funded by the José Carreras International Leukemia Foundation and the Federal Office for Radiation Protection.

The task of the Deutsches Krebsforschungszentrum in Heidelberg (German Cancer Research Center, DKFZ) is to systematically investigate the mechanisms of cancer development and to identify cancer risk factors. The results of this basic research are expected to lead to new approaches in the prevention, diagnosis and treatment of cancer. The Center is financed to 90 percent by the Federal Ministry of Education and Research and to 10 percent by the State of Baden-Wuerttemberg. It is a member of the Helmholtz Association of National Research Centers (Helmholtz-Gemeinschaft Deutscher Forschungszentren e.V.).

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