Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma in the United States. Half of all DLBCLs cannot be cured with the standard immuno-chemotherapeutic regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). 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 DLBCL patients with identical IPI scores exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. The TP53 gene encodes the p53 tumor suppressor, the guardian of the human genome. p53 does not function properly in most human tumors, yet it is inactivated as a direct result of mutations of the TP53 gene in only about 50% of human tumors. Dysregulation of the p53 pathway is important to the pathogenesis of lymphoid malignancies, including DLBCL, though mutations in the TP53 coding sequence occur in about 20% of DLBCL patients. Through our work with the International DLBCL R-CHOP Consortium, which consists of 25 medical centers, we obtained information leading to the hypothesis we propose to test here: genetic and non-genetic biomarkers from the TP53 gene alone or in combination with other abnormalities can predict clinical behavior. In this application, we propose three aims to study the potential of these suspected biomarkers.
In Aim #1, we will determine whether the combination of the IPI and immunohistochemical biomarkers, including p53, is a more clinically accurate model than the IPI alone for predicting DLBCL prognosis.
In Aim #2, we will determine whether the combination of single-nucleotide variants in the TP53 3' untranslated region and mutations in the TP53 coding sequence is a biomarker for DLBCL prognosis.
In Aim #3, we will determine whether circulating miRNAs and cell-free DNA are biomarkers for prognosis and relapse detection for DLBCL. Achieving the aims in this proposal will unravel novel noncoding biomarkers in DLBCL and thereby open a new and unexplored area of investigation for prognosis, treatment decision making, and possibly drug development for a wide range of cancers.
Completing the goals of this proposed study will enhance our understanding of the molecular basis for p53 dysregulation, advance the concept of cancer prognosis and risk biomarkers to include noncoding RNAs and cell-free DNA, and contribute to the development of an improved clinically applicable model for predicting diffuse large B-cell lymphoma patient survival and stratifying patients in clinical trials of new drugs or combination therapies, particularly those with relapsed or refractory disease. The public health implications of these findings are improvement in prognostication for lymphoma and a better understanding of noncoding RNAs in fundamental cancer biology.
