Diffuse large B-cell lymphoma (DLBCL) is the most common and a clinically aggressive lymphoma. In a genome-wide association study (GWAS) of DLBCL, we identified and validated the first genome-wide significant loci for persons of European ancestry at 6p21, 6p25, 8q24 and 2p23. However, the specific functional variant(s) of the GWAS-discovered loci have not been identified, so a next critical step is to fine-map these 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 6p21 were strongly associated with follicular lymphoma (FL), another germinal center lymphoma, and these same SNPs were associated with GCB but not with nonGCB DLBCL. This suggests a shared genetic etiology for FL and GCB-DLBCL at least for some MHC loci. MYC dysregulation through MYC rearrangements, particularly in concert with BCL2 and/or BCL6 rearrangements (?double/triple hit?), as well as aberrant MYC expression are associated with aggressive DLBCL; whether there is heterogeneity of the germline risk variants, particularly at the 8q24 region (location of MYC), by MYC status is unknown. Finally, patients with FL can later develop DLBCL (transformation), which is highly aggressive. We also found that the same SNPs from 6p21 were also associated with an increased risk of FL transformation to DLBCL, which provides new etiologic insights into de novo DLBCL. Comprehensive follow-up of these new and compelling findings provide the rationale and overall goals of our application.
Our aims are: (1) To characterize the newly discovered DLBCL GWAS loci; (2) To evaluate etiologic heterogeneity of genetic risk for DLBCL molecular subtypes; and (3) To evaluate the role of germline 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 SPORE and our established collaborations with InterLymph, MD Anderson, Emory University, LYSA (French Lymphoma Trials Group) and ECOG (Eastern Oncology Group). This proposal is a logical and critical next step to follow-up our novel DLBCL GWAS loci, and will provide new insights into the genetic architecture of risk for DLBCL, DLBCL molecular subtypes, and FL transformation. DLBCL and FL are the two most common lymphoma 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 will have provided unique insights into the shared pathogenesis of FL and GCB-DLBCL, as well as FL transformation to DLBCL. Collectively, our findings should have a major impact on our understanding of DLBCL pathobiology to inform etiologic mechanisms, risk assessment, prevention and treatment. 1

Public Health Relevance

PUBLIC ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive non-Hodgkin lymphoma subtypes. Identifying and understanding genes that increase risk of DLBCL, its biologic subtypes, and follicular transformation to DLBCL, should increase our understanding of the biology of DLBCL and therefore give us better insight into its causes, risk prediction, prevention and treatment. 1

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA200703-03
Application #
9487200
Study Section
Cancer, Heart, and Sleep Epidemiology B Study Section (CHSB)
Program Officer
Carrick, Danielle M
Project Start
2016-07-08
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Shah, Maitri Y; Ferracin, Manuela; Pileczki, Valentina et al. (2018) Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations. Genome Res 28:432-447
Kim, Jongchan; Piao, Hai-Long; Kim, Beom-Jun et al. (2018) Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet 50:1705-1715
McPhail, Ellen D; Maurer, Matthew J; Macon, William R et al. (2018) Inferior survival in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is not associated with MYC/IG gene rearrangements. Haematologica 103:1899-1907
Yuan, T; Yang, Y; Chen, J et al. (2017) Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia 31:2355-2364
Xu, Shengfeng; Wu, Xiao; Wu, Ling et al. (2017) Abro1 maintains genome stability and limits replication stress by protecting replication fork stability. Genes Dev 31:1469-1482
Zang, Shengbing; Li, Jia; Yang, Haiyan et al. (2017) Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis. J Clin Invest 127:2998-3012
Manso, B A; Wenzl, K; Asmann, Y W et al. (2017) Whole-exome analysis reveals novel somatic genomic alterations associated with cell of origin in diffuse large B-cell lymphoma. Blood Cancer J 7:e553
Cerhan, James R; Link, Brian K; Habermann, Thomas M et al. (2017) Cohort Profile: The Lymphoma Specialized Program of Research Excellence (SPORE) Molecular Epidemiology Resource (MER) Cohort Study. Int J Epidemiol 46:1753-1754i