A prospective analysis of peripheral blood cytokines and non-Hodgkin lymphoma

Summary

Principal Investigator: Brenda M Birmann
Abstract: DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of >30 lymphoid neoplasms, >85% of which are of B cell lineage. NHL presents a considerable public health burden with >80,500 new diagnoses and 24,600 deaths expected in 2010. The etiology of NHL is poorly understood, but it is known that overt immune compromise is a strong risk factor. Immune dysregulation may also be important in the etiology of NHL in persons with no overt immune deficiency. The Epstein-Barr virus (EBV) is detected in a sizeable minority of NHL in immune competent persons, but neither the true prevalence nor risk factors for EBV+ NHL are known. Th17, Th1, and Th2 cytokines mediate human immune responses and may be associated with NHL risk by virtue of their roles in B and T lymphocyte activation and inflammation. The Th17 response leads to the induction of several B cell stimulatory cytokines;this axis is also implicated in autoimmune disease, and persons with autoimmune conditions have an increased risk of NHL. It is plausible that Th17 dysregulation, and/or dysregulation of Th1 or Th2 or inflammatory responses, is associated with NHL risk in apparently immune competent adults. Cytokines also mediate host control of EBV and thus may also predict risk of EBV+ NHL. To examine these hypotheses, we will conduct prospective studies nested within the Nurses'Health Study and Health Professionals Follow-up Study cohorts. In a projected pooled sample of 670 cases and 1340 matched controls, we will measure a panel of immune markers in pre-diagnostic plasma samples. We will collect tissue specimens from NHL cases for pathologic studies to determine WHO-defined histologic subtype, diffuse large B-cell lymphoma (DLBCL) molecular subtype, and EBV status. We will use conditional logistic regression to assess the association of plasma immune markers indicative of altered Th17, Th1, Th2 and/or inflammatory responses with NHL. We will evaluate confounding by other NHL risk factors and conduct secondary analyses to examine effect modification and explore the correlation of plasma immune markers with those other factors. With these studies we will be the first to examine the etiologic role of the Th17 response in NHL, to report population-based prevalences of EBV+ NHL by subtype and of DLBCL subtypes, and to prospectively evaluate risk factors for EBV+ NHL. The multidisciplinary study team features epidemiologists (Drs. Birmann, Laden, and Giovannucci), a senior biostatistician (Dr. Rosner), and immunologists (Drs. Martmnez-Maza and Breen) and hematopathologists (Drs. Aster and Rodig) with substantial relevant experience-i.e, in the use of plasma immune markers in etiologic studies, prospective data analysis, and the pathologic determination of NHL histologic type and tumor EBV status. With this highly qualified team, the extraordinary resources of the cohorts, and the proposed studies, we are uniquely situated to contribute novel insights on the role of immune dysregulation in the etiology of NHL and EBV+ NHL in immunocompetent adults.
Funding Period: 2011-09-01 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
    Sonja I Berndt
    Division of Cancer Epidemiology and Genetics, National Cancer Institute NCI, Bethesda, Maryland, USA
    Nat Genet 45:868-76. 2013
  2. pmc A prospective analysis of body size during childhood, adolescence, and adulthood and risk of non-Hodgkin lymphoma
    Kimberly A Bertrand
    Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
    Cancer Prev Res (Phila) 6:864-73. 2013
  3. pmc A pooled analysis of alcohol consumption and risk of multiple myeloma in the international multiple myeloma consortium
    Gabriella Andreotti
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD 20892 9704, USA
    Cancer Epidemiol Biomarkers Prev 22:1620-7. 2013
  4. pmc Temporal stability of serum concentrations of cytokines and soluble receptors measured across two years in low-risk HIV-seronegative men
    Mara M Epstein
    Authors Affiliations Channing Division of Network Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts UCLA AIDS Institute, and Departments of Psychiatry and Biobehavioral Sciences and Obstetrics and Gynecology, David Geffen School of Medicine at UCLA Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania Department of Medicine Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois Departments of Molecular Microbiology and Immunology and Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Department of Microbiology, Immunology and Molecular Genetics, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    Cancer Epidemiol Biomarkers Prev 22:2009-15. 2013
  5. pmc Regular aspirin use and risk of multiple myeloma: a prospective analysis in the health professionals follow-up study and nurses' health study
    Brenda M Birmann
    Channing Division of Network Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115
    Cancer Prev Res (Phila) 7:33-41. 2014

Research Grants

  1. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
  2. Oklahoma Sjogren's Syndrome Center of Research Translation
    KATHY L SIVILS; Fiscal Year: 2013

Detail Information

Publications5

  1. pmc Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
    Sonja I Berndt
    Division of Cancer Epidemiology and Genetics, National Cancer Institute NCI, Bethesda, Maryland, USA
    Nat Genet 45:868-76. 2013
    ..3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism...
  2. pmc A prospective analysis of body size during childhood, adolescence, and adulthood and risk of non-Hodgkin lymphoma
    Kimberly A Bertrand
    Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
    Cancer Prev Res (Phila) 6:864-73. 2013
    ..01). These findings in two large prospective cohorts provide novel evidence that larger body size in childhood, adolescence, and young adulthood predicts increased risk of NHL, and particularly of DLBCL and follicular lymphoma...
  3. pmc A pooled analysis of alcohol consumption and risk of multiple myeloma in the international multiple myeloma consortium
    Gabriella Andreotti
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD 20892 9704, USA
    Cancer Epidemiol Biomarkers Prev 22:1620-7. 2013
    ..Recent findings suggest that alcohol consumption may reduce risk of multiple myeloma...
  4. pmc Temporal stability of serum concentrations of cytokines and soluble receptors measured across two years in low-risk HIV-seronegative men
    Mara M Epstein
    Authors Affiliations Channing Division of Network Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts UCLA AIDS Institute, and Departments of Psychiatry and Biobehavioral Sciences and Obstetrics and Gynecology, David Geffen School of Medicine at UCLA Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania Department of Medicine Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois Departments of Molecular Microbiology and Immunology and Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Department of Microbiology, Immunology and Molecular Genetics, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    Cancer Epidemiol Biomarkers Prev 22:2009-15. 2013
    ..Estimates of the within-person temporal stability of serum markers partly assess the utility of single biomarker measurements and may have important implications for the design of prospective studies of chronic disease risk...
  5. pmc Regular aspirin use and risk of multiple myeloma: a prospective analysis in the health professionals follow-up study and nurses' health study
    Brenda M Birmann
    Channing Division of Network Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115
    Cancer Prev Res (Phila) 7:33-41. 2014
    ..e., NF-κB- or COX-2 mediated) pathways. The utility of aspirin for multiple myeloma chemoprevention warrants further evaluation...

Research Grants30

  1. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..
  2. Oklahoma Sjogren's Syndrome Center of Research Translation
    KATHY L SIVILS; Fiscal Year: 2013
    ..This will in turn create opportunities for new diagnostics, prognostic and therapeutic strategies that will benefit patients with this and other related diseases. ..