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 #
3P50CA097274-11S1
Application #
8561353
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
2002-09-20
Project End
2017-06-30
Budget Start
2012-09-12
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$10,064
Indirect Cost
$3,399
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Thanarajasingam, Gita; Maurer, Matthew J; Farooq, Umar et al. (2018) Event-free survival at 24 months captures central nervous system relapse of systemic diffuse large B-cell lymphoma in the immunochemotherapy era. Br J Haematol 183:149-152
Kleinstern, Geffen; Maurer, Matthew J; Liebow, Mark et al. (2018) History of autoimmune conditions and lymphoma prognosis. Blood Cancer J 8:73
Saad Aldin, Ehab; McNeely, Parren; Menda, Yusuf (2018) Posterior Reversible Encephalopathy Syndrome on 18F-FDG PET/CT in a Pediatric Patient With Burkitt's Lymphoma. Clin Nucl Med 43:195-198
Link, Brian K; Day, Bann-Mo; Zhou, Xiaolei et al. (2018) Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study. Br J Haematol :
Ebeid, Kareem; Meng, Xiangbing; Thiel, Kristina W et al. (2018) Synthetically lethal nanoparticles for treatment of endometrial cancer. Nat Nanotechnol 13:72-81
Holahan, Heather M; Farah, Ronda S; Fitz, Sara et al. (2018) Health-related quality of life in patients with cutaneous T-cell lymphoma? Int J Dermatol 57:1314-1319
Maurer, Matthew J; Ghesquières, Hervé; Link, Brian K et al. (2018) Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials. J Clin Oncol 36:1603-1610
Huet, Sarah; Tesson, Bruno; Jais, Jean-Philippe et al. (2018) A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts. Lancet Oncol 19:549-561
El-Galaly, Tarec Christoffer; Cheah, Chan Yoon; Bendtsen, Mette Dahl et al. (2018) Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma. Eur J Cancer 93:57-68
Mackrides, Nicholas; Chapman, Jennifer; Larson, Melissa C et al. (2018) Prevalence, clinical characteristics and prognosis of EBV-positive follicular lymphoma. Am J Hematol :

Showing the most recent 10 out of 387 publications