Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype. It is well established that there are driver somatic mutations in DLBCL etiology and prognosis, as well as a role for germline genetic susceptibility. In fact, early results from candidate gene association studies have shown a promising role for common genetic variants in immune and apoptotic genes in NHL. In the last funding cycle, we identified SNPs in BCL2L11 (BIM), CASP9, and APAF1 that were associated with increased risk in our SPORE case-control study. Resequencing of these genes in the tumors of 40 DLBCL patients identified novel genomic alterations, and in Aim 1 we propose to characterize the etiologic and therapeutic significance of these novel mutations with laboratory-based studies.
In Aim 2 and 3, we propose a comprehensive and agnostic strategy that integrates both somatic and germline genetics in order to identify additional novel risk variants. We will do this by leveraging our SPORE's involvement in the large International Lymphoma Epidemiology (InterLymph) consortium genome-wide association study (GWAS) of DLBCL (>S000 cases and 10,000 controls) and our whole-exome next generation sequencing (NGS) study of paired tumor and germline DLBCL cases (N=77). The GWAS is powered to identify common variants, and the NGS study will allow us to identify lower frequency variants, defined here as 0.5% to 5%. Using a multistage design in Aim 2, we propose to identify novel gennline low-frequency variants associated with risk of developing DLBCL, and in Aim 3, we identify and validate somatically acquired driver mutations in genes critical to DLBCL pathogenesis. In exploratory analyses, we will evaluate pathways and the role of these variants in DLBCL prognosis. This proposal utilizes the unique resources of our SPORE, the InterLymph GWAS, and our DLBCL whole-exome NGS project. We have an outstanding team with a strong track record of interdisciplinary genetics work in lymphoma and have demonstrated the ability to integrate genetic epidemiology with lab-based functional work. Our study builds on several novel findings from the prior study period, but also expands to fill an important need in the genetic epidemiology of DLBCL as the first comprehensive study of low frequency germline variants in risk. Low frequency variants, either individually or cumulatively across a gene, and in combination with common variants, are likely to inform etiologic pathways and clinical risk assessment. Furthermore, we will identify novel driver mutations in genes and pathways from DLBCL tumors that can inform tumor biology and identify novel treatment targets. In summary, as the first comprehensive study of both germline and somatic genetic variants in DLBCL, we are likely to provide new and unexpected insights into lymphomagenesis, which can then be exploited clinically for risk assessment, prognostic stratification and identification of new treatment targets.

Public Health Relevance

As the first comprehensive study of both germline and somatic genetic variants in DLBCL, we are likely to provide new and unexpected insights into lymphomagenesis, which can then be exploited clinically for risk assessment, prognostic stratification and identification of new treatment targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA097274-11
Application #
8395827
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
2002-09-11
Project End
2017-06-30
Budget Start
2012-09-12
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$289,528
Indirect Cost
$26,203
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Link, Brian K (2017) Early Relapse in Follicular Lymphoma: High Risks and High Stakes. J Oncol Pract 13:810-811
Ding, Wei; LaPlant, Betsy R; Call, Timothy G et al. (2017) Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 129:3419-3427
Ammann, Eric M; Shanafelt, Tait D; Larson, Melissa C et al. (2017) Time to Second-line Treatment and Subsequent Relative Survival in Older Patients With Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Clin Lymphoma Myeloma Leuk 17:e11-e25
Wafa, Emad I; Geary, Sean M; Goodman, Jonathan T et al. (2017) The effect of polyanhydride chemistry in particle-based cancer vaccines on the magnitude of the anti-tumor immune response. Acta Biomater 50:417-427
Paulus, A; Akhtar, S; Yousaf, H et al. (2017) Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment. Blood Cancer J 7:e565
Tanaka, Yoshimasa; Iwasaki, Masashi; Murata-Hirai, Kaoru et al. (2017) Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug. Sci Rep 7:5987
Wang, Xueju; Dasari, Surendra; Nowakowski, Grzegorz S et al. (2017) Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma. Oncotarget 8:26245-26255
Scott, David W; Abrisqueta, Pau; Wright, George W et al. (2017) New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies. J Clin Oncol 35:1668-1677
Tracy, S I; Maurer, M J; Witzig, T E et al. (2017) Vitamin D insufficiency is associated with an increased risk of early clinical failure in follicular lymphoma. Blood Cancer J 7:e595
Law, Philip J; Berndt, Sonja I; Speedy, Helen E et al. (2017) Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nat Commun 8:14175

Showing the most recent 10 out of 337 publications