Non-Hodgkin Lymphoma (NHL) incidence and mortality have been increasing over the past 50 years, and these trends are largely unexplained. The five-year survival rates are 50% overall, and appear to have changed little over the last several decades. For NHL, a compelling hypothesis is that survival may be related to the host immune status, which is in part influenced by functional polymorphisms in genes encoding cytokines and chemokines central to immune function and regulation. The role for host immunogenetic susceptibility in overall survival from NHL is largely unexplored. We propose to systematically test the hypothesis that genes with functional, common variant polymorphisms involved in immune function and regulation are associated with overall survival from NHL.
Our specific aims are: 1) to evaluate the association of polymorphisms in selected immune-related genes from four key pathways on NHL survival that include genes encoding inflammatory and regulatory cytokines (IL-1A IL-1B IL-1RN TNFalpha), Th1/Th2 cytokines (LTA, INFgamma IL-4, IL-4RA IL-6 iL-JO, IL-13), innate immunity (MPO, ICAM-1) and chemokines (IL-8, SDF-1, CCR2, CCR5); 2) to evaluate whether any effects are independent of other NHIL prognostic factors (e.g., age, stage, ECOG performance status, extranodal site involvement, and serum LDH), and treatment modality; and 3) to evaluate whether any effects are specific for diffuse large B-cell lymphoma or the combination of follicular and small lymphocytic lymphoma. To achieve these aims, we will develop a prognostic cohort using 364 HIV-negative NHL patients who participated in a population-based case-control study in Iowa. The patients were aged 20-74 years when first diagnosed from 1998-2000. We will abstract treatment and other clinical/laboratory prognostic data from the medical record. We will follow all of these patients by both passive and active means through mid-2006 (a minimum of 6.5 years) in order to identify all deaths (including cause of death) and disease recurrences. Genotyping will be conducted in conjunction with the investigators at the National Cancer Institute. The association of genotype frequencies with NEIL survival will be evaluated using standard survival analysis approaches, and we have sufficient statistical power to detect clinically meaningful hazard ratios. In summary, we will evaluate innovative translational hypotheses regarding the immunogenetic determinants of NEIL survival in order to better understand disease pathogenesis, treatment response, and disease prognosis among patients from the community.
