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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092153-10
Application #
8289640
Study Section
Special Emphasis Panel (ZRG1-HOP-N (03))
Program Officer
Divi, Rao L
Project Start
2001-07-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$562,598
Indirect Cost
$190,263
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Machiela, Mitchell J; Lan, Qing; Slager, Susan L et al. (2016) Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes. Hum Mol Genet 25:1663-76
Solomon, B M; Chaffee, K G; Moreira, J et al. (2016) Risk of non-hematologic cancer in individuals with high-count monoclonal B-cell lymphocytosis. Leukemia 30:331-6
Gupta, M; Stenson, M; O'Byrne, M et al. (2016) Comprehensive serum cytokine analysis identifies IL-1RA and soluble IL-2Rα as predictors of event-free survival in T-cell lymphoma. Ann Oncol 27:165-72
Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F et al. (2016) Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia. Nat Commun 7:10933
Kane, Eleanor; Skibola, Christine F; Bracci, Paige M et al. (2015) Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium. Cancer Epidemiol Biomarkers Prev 24:1061-70
Atkinson, Elizabeth J; Eckel-Passow, Jeanette E; Wang, Alice et al. (2015) The association of copy number variation and percent mammographic density. BMC Res Notes 8:297
Boddicker, Rebecca L; Kip, N Sertac; Xing, Xiaoming et al. (2015) The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma. Blood 125:3118-27
Wang, Sophia S; Vajdic, Claire M; Linet, Martha S et al. (2015) Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci. Am J Epidemiol 181:406-21
Vijai, Joseph; Wang, Zhaoming; Berndt, Sonja I et al. (2015) A genome-wide association study of marginal zone lymphoma shows association to the HLA region. Nat Commun 6:5751
(2015) Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types. J Natl Cancer Inst 107:djv279

Showing the most recent 10 out of 75 publications