Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the United States. Although the risk of developing NHL is greatly elevated in the setting of overt immunosuppression, the great majority of NHL, and in particular B cell NHL, occur in individuals who appear to be immunocompetent. Relatively little is known about the etiology of the B cell NHL that arise de novo in immunocompetent populations. Epstein-Barr virus (EBV), a B cell-tropic gamma-herpesvirus, is clearly implicated in the etiology of NHL in immunosuppressed individuals, with such tumors often having detectable clonal EBV DNA or gene products. However, only a minority (approximately 5%) of the NHL seen in presumably immunocompetent individuals are EBV genome-positive, and most of these are non-B cell NHL, so the role of EBV in the etiology of NHL in such individuals is less clear. The overall goal of this study is to determine whether an immune system environment that promotes chronic B cell stimulation, and/or results in poorly-controlled Epstein-Barr virus (EBV) infection, will lead to an increased risk of B cell NHL. Chronic B cell stimulation can increase the occurrence of B cell DNA-modifying activities, thereby increasing the probability for the generation of molecular errors (translocations or mutations of oncogenes) that initiate these cancers. Another mechanism that could promote such genetic errors is loss of immunoregulatory control of EBV infection, as EBV can promote lymphomagenesis by the infection and transformation of B cells, as well as via the up-regulation of the expression of molecules that induce somatic hypermutation and subsequent oncogene mutation.
The specific aims of this study are: 1) determine if indicators of likely B-cell activation, including elevated serum levels of B cell-stimulatory cytokines and/or of molecules that are associated with B cell activation, are associated with the subsequent development of B cell NHL (diffuse large B cell lymphoma [DLBCL] and follicular lymphoma) in apparently immunocompetent individuals; 2) determine whether altered patterns of antibodies to EBV, consistent with reactivation of EBV, are seen preceding the development of B cell NHL (DLBCL and follicular lymphoma), and 3) define the temporal relationship between changes in these biomarkers and the development of DLBCL and follicular lymphoma.
These aims will be addressed in a nested case-control study (approximately 600 incident B cell NHL cases and 600 matched controls) using serial pre-diagnosis serum specimens archived in the Department of Defense Serum Repository. Therefore, this investigation will provide a window on host and viral factors during the critical period of B cell NHL pathogenesis by repeated assessment of sequential specimens prior to diagnosis. Our approach is to assess a range of immunity- and EBV-related biomarkers in serial specimens, as a means of detecting """"""""bio- footprints"""""""" leading to disease. These studies should provide valuable insight on the role of immune dysfunction and/or loss of immunoregulatory control of EBV infection on the development of B cell NHL. ? ? ? ? ? ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121195-02
Application #
7293557
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Jessup, John M
Project Start
2006-09-29
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$358,114
Indirect Cost
Name
University of California Los Angeles
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Levin, Lynn I; Breen, Elizabeth C; Birmann, Brenda M et al. (2017) Elevated Serum Levels of sCD30 and IL6 and Detectable IL10 Precede Classical Hodgkin Lymphoma Diagnosis. Cancer Epidemiol Biomarkers Prev 26:1114-1123
Epeldegui, Marta; Lee, Jeannette Y; Martínez, Anna C et al. (2016) Predictive Value of Cytokines and Immune Activation Biomarkers in AIDS-Related Non-Hodgkin Lymphoma Treated with Rituximab plus Infusional EPOCH (AMC-034 trial). Clin Cancer Res 22:328-36
Edlefsen, Kerstin L; Martínez-Maza, Otoniel; Madeleine, Margaret M et al. (2014) Cytokines in serum in relation to future non-Hodgkin lymphoma risk: evidence for associations by histologic subtype. Int J Cancer 135:913-22
Vendrame, Elena; Hussain, Shehnaz K; Breen, Elizabeth Crabb et al. (2014) Serum levels of cytokines and biomarkers for inflammation and immune activation, and HIV-associated non-Hodgkin B-cell lymphoma risk. Cancer Epidemiol Biomarkers Prev 23:343-9
Hussain, Shehnaz K; Zhu, Weiming; Chang, Shen-Chih et al. (2013) Serum levels of the chemokine CXCL13, genetic variation in CXCL13 and its receptor CXCR5, and HIV-associated non-hodgkin B-cell lymphoma risk. Cancer Epidemiol Biomarkers Prev 22:295-307
Daniels, Tracy R; Martínez-Maza, Otoniel; Penichet, Manuel L (2012) Animal models for IgE-meditated cancer immunotherapy. Cancer Immunol Immunother 61:1535-46
Daniels, Tracy R; Leuchter, Richard K; Quintero, Rafaela et al. (2012) Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells. Cancer Immunol Immunother 61:991-1003
Vendrame, Elena; Martinez-Maza, Otoniel (2011) Assessment of pre-diagnosis biomarkers of immune activation and inflammation: insights on the etiology of lymphoma. J Proteome Res 10:113-9
Vajdic, Claire M; Falster, Michael O; de Sanjose, Silvia et al. (2009) Atopic disease and risk of non-Hodgkin lymphoma: an InterLymph pooled analysis. Cancer Res 69:6482-9