ENVIRONMENTAL & GENETIC RISK FACTORS OF LYMPHOMA LATEST FINDINGS FROM THE INTERLYMPH CONSORTIUM 2014
Karin E Smedby, M.D., Ph.D. Associate professor, Karolinska Institutet Unit of Clinical Epidemiology, Dept of Medicine Solna Consultant, Hematology center, Karolinska University Hospital, Stockholm, Sweden Chair, Coordinating Committee, International Lymphoma Epidemiology (InterLymph) Consortium
What is InterLymph?
The International Lymphoma Epidemiology Consortium (InterLymph) is an open scientific forum for epidemiologic research in malignant lymphoma. Established in 2001, the Consortium is an international collaboration of scientists who undertake research projects that pool data across studies to better understand lymphoma risk factors. Although the main emphasis of the collaboration is epidemiology, InterLymph has expanded to include geneticists, pathologists, immunologists, clinicians and other scientists and now includes more than 100 members. InterLymph consists of four working groups (Immunology and Infection, lifestyle and environment, pathology and survival, genetics), and has evolved to include multiple large scale projects that operate across working groups. In 2014, several large pooling projects have been successfully finalized (see below).
What are the goals of InterLymph?
The overarching goal of InterLymph is to identify patterns of commonality and heterogeneity in the etiology of lymphoma subtypes which may assist in illustrating mechanisms of the development of lymphoma. This knowledge has implications for understanding biology, etiology, prevention and control of these malignancies. The Consortium aims to achieve this by addressing research questions that are difficult to answer in individual studies, by sharing data and biological samples. The Consortium has established a central data coordinating center that is a repository of pooled, harmonised data from all recently completed international case-control studies of lymphoma. In recent years, the collaboration has also expanded to several international cohort studies.
Latest findings from InterLymph
In the largest pooling project of environmental etiology so far conducted in the history of InterLymph (the InterLymph Non-Hodgkin Lymphoma subtypes project), medical history, lifestyle, family history and occupational risk factors were investigated for risk of 11 non-Hodgkin lymphoma (NHL) subtypes (Journal of the National Cancer Institute Monograph August 2014). In addition, etiologic heterogeneity among subtypes was assessed using novel statistical methods. The analysis involved 17,471 lymphoma patients and 23,096 controls recruited in 20 case-control studies in North America, Europe and Australia. Risks differed significantly among NHL subtypes for medical history factors, alcohol consumption, cigarette smoking and certain occupations, whereas generally similar risks were observed for family history of lymphoma, recreational sun exposure, hay fever, allergy and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas, but there were also substantial differences among B-cell lymphomas.
Several large-scale investigations of genetic risk factors for lymphoma subtypes were also published in 2014. A pooled genome-wide association study (GWAS) was conducted for diffuse large B-cell lymphoma which included 5,216 cases and 12,223 controls of European ancestry (Cerhan et al, Nature Genetics 2014). Five independent risk SNPs in four loci were identified (in or nearby the genes EXOC2, HLA-B, NCOA1 and PVT1). The results point towards genetic pathways involved in immune recognition and immune function in the pathogenesis of diffuse large B-cell lymphoma. In another pooled study of genetic variation in risk of follicular lymphoma (4,523 cases and 13,344 controls), a strong association with variation in the human leukocyte antigen (HLA) region was confirmed. In addition, for the first time, risk loci were also identified outside of the HLA region, near or in the genes CXCR5, ETS1, LPP, BCL2 and PVT1. These findings implicate a role for genetic regions involved in lymphocyte biology and survival in follicular lymphoma risk. A third study investigated genetic variation in risk of Hodgkin lymphoma (Cozen et al, Nature Communications, 2014). Here, a novel variant was identified at 19p13.3 located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in Hodgkin lymphoma pathogenesis. These findings will help to elucidate mechanisms of development of lymphoma subtypes, and to understand patterns of gene-environment interaction.