Etiologic heterogeneity among non-hodgkin lymphoma subtypes: The interLymph non-hodgkin lymphoma subtypes project

Lindsay M. Morton, Susan L. Slager, James R. Cerhan, Sophia S. Wang, Claire M. Vajdic, Christine F. Skibola, Paige M. Bracci, Silvia de Sanjosé, Karin E. Smedby, Brian C.H. Chiu, Yawei Zhang, Sam M. Mbulaiteye, Alain Monnereau, Jennifer J. Turner, Jacqueline Clavel, Hans Olov Adami, Ellen T. Chang, Bengt Glimelius, Henrik Hjalgrim, Mads MelbyePaolo Crosignani, Simonetta di Lollo, Lucia Miligi, Oriana Nanni, Valerio Ramazzotti, Stefania Rodella, Adele Seniori Costantini, Emanuele Stagnaro, Rosario Tumino, Carla Vindigni, Paolo Vineis, Nikolaus Becker, Yolanda Benavente, Paolo Boffetta, Paul Brennan, Pierluigi Cocco, Lenka Foretova, Marc Maynadié, Alexandra Nieters, Anthony Staines, Joanne S. Colt, Wendy Cozen, Scott Davis, Anneclaire J. de Roos, Patricia Hartge, Nathaniel Rothman, Richard K. Severson, Elizabeth A. Holly, Timothy G. Call, Andrew L. Feldman, Thomas M. Habermann, Mark Liebow, Aaron Blair, Kenneth P. Cantor, Eleanor V. Kane, Tracy Lightfoot, Eve Roman, Alex Smith, Angela Brooks-Wilson, Joseph M. Connors, Randy D. Gascoyne, John J. Spinelli, Bruce K. Armstrong, Anne Kricker, Theodore R. Holford, Qing Lan, Tongzhang Zheng, Laurent Orsi, Luigino Dal Maso, Silvia Franceschi, Carlo La Vecchia, Eva Negri, Diego Serraino, Leslie Bernstein, Alexandra Levine, Jonathan W. Friedberg, Jennifer L. Kelly, Sonja I. Berndt, Brenda M. Birmann, Christina A. Clarke, Christopher R. Flowers, James M. Foran, Marshall E. Kadin, Ora Paltiel, Dennis D. Weisenburger, Martha S. Linet, Joshua N. Sampson

Research output: Contribution to journalArticlepeer-review


Background: Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. Methods: We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (PNODE). Results: Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (PNODE < 1.0 × 10-4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (PNODE < 1.0 × 10-4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Conclusions: Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

Original languageAmerican English
Pages (from-to)130-144
Number of pages15
JournalJournal of the National Cancer Institute. Monographs
Issue number48
StatePublished - Aug 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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