Genetic Epidemiology of non-Hodgkin Lymphoma

Project: Research projectResearch Project

Description

ABSTRACTDiffuse large B-cell lymphoma (DLBCL) is the most common and a clinically aggressive lymphoma. In agenome-wide association study (GWAS) of DLBCL, we identified and validated the first genome-widesignificant loci for persons of European ancestry at 6p21, 6p25, 8q24 and 2p23. However, the specificfunctional variant(s) of the GWAS-discovered loci have not been identified, so a next critical step is to fine-mapthese regions and conduct a bioinformatics analysis to characterize potential genetic drivers. Furthermore,DLBCL is biologically and clinically heterogeneous, with this heterogeneity in part defined by cell-of-origin(COO) and MYC status. COO derives from gene expression studies and has two dominant subtypes ?germinal center (GCB) and nonGCB. In preliminary data from our immunogenetic studies, SNPs from 6p21were strongly associated with follicular lymphoma (FL), another germinal center lymphoma, and these sameSNPs were associated with GCB but not with nonGCB DLBCL. This suggests a shared genetic etiology for FLand GCB-DLBCL at least for some MHC loci. MYC dysregulation through MYC rearrangements, particularly inconcert with BCL2 and/or BCL6 rearrangements (?double/triple hit?), as well as aberrant MYC expression areassociated with aggressive DLBCL; whether there is heterogeneity of the germline risk variants, particularly atthe 8q24 region (location of MYC), by MYC status is unknown. Finally, patients with FL can later developDLBCL (transformation), which is highly aggressive. We also found that the same SNPs from 6p21 were alsoassociated with an increased risk of FL transformation to DLBCL, which provides new etiologic insights into denovo DLBCL. Comprehensive follow-up of these new and compelling findings provide the rationale and overallgoals of our application. Our aims are: (1) To characterize the newly discovered DLBCL GWAS loci; (2) Toevaluate etiologic heterogeneity of genetic risk for DLBCL molecular subtypes; and (3) To evaluate the role ofgermline genetic variants and tumor markers with risk of transformation from FL to DLBCL. To meet our aims,we will use the existing and ongoing resources of the Mayo Case-Control Study and the Iowa-Mayo SPOREand our established collaborations with InterLymph, MD Anderson, Emory University, LYSA (FrenchLymphoma Trials Group) and ECOG (Eastern Oncology Group). This proposal is a logical and critical nextstep to follow-up our novel DLBCL GWAS loci, and will provide new insights into the genetic architecture of riskfor DLBCL, DLBCL molecular subtypes, and FL transformation. DLBCL and FL are the two most commonlymphoma subtypes, and FL transformation is an important clinical problem. At the completion of this project,we expect to have defined the location of risk SNPs for DLBCL and its molecular subtypes. Further, we willhave provided unique insights into the shared pathogenesis of FL and GCB-DLBCL, as well as FLtransformation to DLBCL. Collectively, our findings should have a major impact on our understanding ofDLBCL pathobiology to inform etiologic mechanisms, risk assessment, prevention and treatment.1
StatusActive
Effective start/end date7/8/165/31/21

Funding

  • National Institutes of Health: $686,290.00

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Follicular Lymphoma
Molecular Epidemiology
Non-Hodgkin's Lymphoma
Genome-Wide Association Study
Single Nucleotide Polymorphism
Germinal Center
Lymphoma
Immunogenetics
Genetic Heterogeneity
B-Cell Lymphoma
Tumor Biomarkers
Computational Biology
Genetic Markers
Case-Control Studies
Genome
Gene Expression