BA13 - Markers of B-cell stimulation as potential predictors of Non-Hodgkins lymphoma

Investigator Names and Contact Information

Anneclaire DeRoos (deroos@u.washington.edu)

Introduction/Intent

Our goal is to further elucidate the etiology of B-cell non-Hodgkin lymphoma (NHL), the most common type of lymphoma. One factor that is well-understood to cause NHL is altered immunity – as evidenced by increased rates of NHL among clinically immunocompromised patients, including persons with AIDS and transplant recipients.1 The importance of subclinical immune dysregulation in development of NHL among immunocompetent persons is unclear, and investigations were until recently limited to crude indicators of immune system development or function such as the number of siblings to indicate early life infection,2 or classification of persons by conditions in their medical history. With rapidly developing technology in sensitive and/or high-throughput methods for detection of molecular and protein markers, greater opportunities exist to describe subtle variation of the host immune environment. In this new era of discovery, there is increasing evidence that subclinically altered immunity is involved in the development of NHL among immunocompetent persons, through observed associations with variants in genes regulating cytokine production.

Another way of characterizing subclinical immune dysregulation is to describe the immune milieu within a person in terms of the levels of cytokines, chemokines, and viruses. This type of study would aim to identify subtle shifts in the host immune environment within one group of persons (e.g., cases) as compared to the average levels in a comparison group (e.g., controls) – thus describing the immune environment with greater specificity than by categorizations based on medical history. However, this type of study can only give valid clues to etiology when conducted within a prospective cohort in which markers are measured in prediagnostic samples. Thus, the design of the Women’s Health Initiative (WHI) Observational Study (OS) and the banked samples offer a valuable resource to identify markers of subclinical immune dysregulation that are associated with NHL development.

Our proposed research was inspired by previous prospective studies that have found markers of B-cell stimulation to be predictive of NHL. Studies conducted among AIDS patients found that certain cytokines, chemokines, and other molecules that reflect B-cell activation were strongly predictive of which patients developed NHL.4-13 Epstein-Barr virus (EBV), which in its active form is characterized by B-cell proliferation, has also been associated with NHL, in three prospective cohort studies of immunocompetent persons in which aberrant levels of antibodies to EBV antigens were predictive of NHL.14-16 In addition, poor regulation of EBV infection among transplant recipients, as monitored by viral DNA load, is an important predictor of development of lymphoproliferative disorders.17;18 Based on the findings of these studies, we hypothesize that a chronic B-cell stimulatory host environment increases the risk of B-cell NHL among immunocompetent persons. We propose to investigate our hypothesis among women in the WHI OS, using biologic samples collected an average of 10 years before NHL diagnosis.

We hypothesize that subclinical immune dysregulation, characterized by a chronic B-cell stimulatory host environment, is a central etiologic pathway for B-cell NHL, resulting from increased chances of genetic errors that occur during the processes of B-cell proliferation, immunoglobulin (Ig) class switching, and Ig somatic hypermutation.

Specific aims:

1. Evaluate the risk of B-cell NHL associated with immune parameters, measured in prediagnostic plasma/serum, that are indicative of a B-cell stimulatory host environment, including levels of certain cytokines (e.g., IL6, IL10, TNFα), cytokine-like molecules (sCD23), soluble cytokine receptors (sCD27, sCD30), and other molecules involved in B-cell response (sCD44, CXCL13).
2. Measure EBV DNA load and antibodies to key EBV antigens (VCA, EBNA1, and EA-D), for estimation of the risk of B-cell NHL associated with EBV, a cause of B-cell proliferation.
3. Investigate whether observed associations differ by major NHL subtype, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), and marginal zone lymphoma.

Secondary aim:

4. Describe the patterns of association between immune/EBV markers and B-cell NHL, according to the number of years between blood sample collection and NHL diagnosis.

Results/Findings Some of the publications related to this ancillary study are: 1374. For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.