Non-Hodgkin lymphoma (NHL) is now the 5th most frequently diagnosed cancer among both men and women in the US. There is rapidly accumulating evidence for several candidate susceptibility genes in the etiology of NHL, supporting a polygenic model based on low-penetrance alleles in line with the common-variant, common- disease hypothesis. In parallel, much progress has been made in uncovering environmental risk factors for this cancer, and the field is maturing to the point of beginning to evaluate gene-environment interactions. This application is a request for renewal of R01 CA92153 to allow us to continue our investigation into the etiology of this important cancer. We have made major progress on the scientific and operational goals from the original grant. The goal of this renewal is to increase our understanding of the genetic and environmental etiology of NHL by building on several key leads from the last grant cycle. There are four specific aims: 1) To evaluate the association of inherited variability in inflammation and immune genes with risk of NHL; 2) To evaluate epidemiologic risk factors for NHL, with a focus on medical history (including aspirin and NSAID use, immunization history, and statin use), energy balance (including obesity and physical activity), diet (including antioxidant-related nutrients and flavonoids), and farming/pesticide exposure (including farm practices and exposure to phenoxyacetic acid and triazine herbicides and organophosphate insecticides); 3) To evaluate gene-environment interactions in the etiology of NHL, with a focus on the interaction of immune-related genes with immunologic diseases/conditions and the interaction of genes involved in carcinogen metabolism and detoxification pathways with antioxidant-related dietary factors; and 4) To validate selected genetic and epidemiologic risk factor findings from this renewal in the InterLymph Consortium, including the top 20 single nucleotide polymorphisms (SNPs) from Aim 1. To achieve these aims, we will utilize our ongoing, clinic-based case-control study of NHL. Through April 2007, we have enrolled 940 NHL cases and 1,197 controls, and by the completion of this renewal application, we will have an estimated 2,000 NHL cases and 2,000 controls. We have built an outstanding resource, with central phenotypic definition by expert hematopathologists, extensive collection of biologic samples and risk factor data, access to state-of-the-art bioinformatics and genotyping, and an established, interdisciplinary study team. In this renewal, we will have excellent power to test our a priori hypotheses, and we will use a two-stage design for our genetic studies to increase efficiency. We are fully engaged in the InterLymph Consortium by contributing data for pooled studies, as well as taking leadership roles in several initiatives. The pooling activities of the consortium are critical for replication in large, independent samples, in order to more rapidly advance the field and to adequately address hypotheses related to NHL subtypes. Completion of the renewal aims will significantly advance our understanding of the etiology of this cancer, and should help identify new approaches for the prevention and control of NHL. PUBLIC HEALTH RELEVANCE: Non-Hodgkin lymphoma (NHL) is an important cancer in the United States, and we only partially understand the genetic and environmental risk factors for this malignancy. We will build off the progress from the previous funding period, and completion of our renewal aims will significantly advance our understanding of the etiology of this cancer, and should help identify new approaches for the prevention and control of NHL.