MYC as a Biomarker in Aggressive Non-Hodgkin Lymphoma Project Abstract Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy, constituting about 4.6% of human cancers and causing about 3.5% of all cancer deaths in the United States. The incidence of NHL has increased by more than 80% between 1975 and 1991 in the United States - one of the largest increases of any cancer (SEER Cancer Statistics Review 1975-2004). Although there are more than 50 types of NHLs, diffuse large B cell lymphoma (DLBCL) is the most common, accounting for approximately 35 percent of all NHLs. In the United States, DLBCL affects about 7 out of 100,000 people each year. Half of DLBCL patients cannot be cured with the standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Currently the most common tool for determining DLBLC prognosis is the International Prognostic Index (IPI), which is based on five clinical characteristics (patient age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites). Yet patients with identical IPI scores exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. Deregulation of MYC, the gene that encodes the c-Myc transcription factor, through translocation, amplification, or other mechanisms is important in the pathogenesis of lymphoid malignancies, including DLBCL. We have assembled an International DLBCL R-CHOP Consortium with 25 medical centers and have established ourselves as a leading team specializing in DLBCL biomarkers. We hypothesize that MYC is a biomarker for DLBCL prognosis and risk-adjusted therapies. In this application, we propose three aims to ascertain the potential of genetic and non-genetic alteration of MYC in DLBCL prognosis and therapy.
In Aim 1, we will determine the comprehensive role of MYC in DLBCL prognosis using 3,000 specimens.
In Aim 2, we will determine whether DLBCL with MYC translocation differs from those without MYC translocation in gene expression and treatment response.
In Aim 3, we will determine the molecular basis of differential prognostic values of MYC CDS and 3'UTR mutations in DLBCL.

Public Health Relevance

MYC as a Biomarker in Aggressive Non-Hodgkin Lymphoma Project Narrative Completing the goals in this research plan will advance the concept of cancer prognosis and risk biomarkers to include the beneficial effect of gene mutation and result in an improved clinically applicable model for stratifying DLBCL patients for drug development and risk-adjusted therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA187415-04
Application #
9451245
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Agrawal, Lokesh
Project Start
2015-04-20
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Zhang, Jun; Medeiros, L Jeffrey; Young, Ken H (2018) Cancer Immunotherapy in Diffuse Large B-Cell Lymphoma. Front Oncol 8:351
Yao, Z; Deng, L; Xu-Monette, Z Y et al. (2018) Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy. Leukemia 32:353-363
Xu-Monette, Zijun Y; Zhou, Jianfeng; Young, Ken H (2018) PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood 131:68-83
Cai, Qingqing; Tu, Meifeng; Xu-Monette, Zijun Y et al. (2017) NF-?B p50 activation associated with immune dysregulation confers poorer survival for diffuse large B-cell lymphoma patients with wild-type p53. Mod Pathol 30:854-876
Xu-Monette, Zijun Y; Zhang, Mingzhi; Li, Jianyong et al. (2017) PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response? Front Immunol 8:1597
Ok, Chi Young; Young, Ken H (2017) Targeting the programmed death-1 pathway in lymphoid neoplasms. Cancer Treat Rev 54:99-109
Yu, Li; Tu, Meifeng; Cortes, Jorge et al. (2017) Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease. Blood 129:1658-1668
Yu, Li; Li, Ling; Medeiros, L Jeffrey et al. (2017) NF-?B signaling pathway and its potential as a target for therapy in lymphoid neoplasms. Blood Rev 31:77-92
Wang, Jinfen; Xu-Monette, Zijun Y; Jabbar, Kausar J et al. (2017) AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma. Am J Pathol 187:1700-1716
Cao, Xin; Medeiros, L Jeffrey; Xia, Yi et al. (2016) Clinicopathologic features and outcomes of lymphoplasmacytic lymphoma patients with monoclonal IgG or IgA paraprotein expression. Leuk Lymphoma 57:1104-13

Showing the most recent 10 out of 22 publications