Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study.

Abstract

TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.

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Published Version (Please cite this version)

10.1182/blood-2012-05-433334

Publication Info

Xu-Monette, Zijun Y, Lin Wu, Carlo Visco, Yu Chuan Tai, Alexander Tzankov, Wei-min Liu, Santiago Montes-Moreno, Karen Dybkaer, et al. (2012). Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood, 120(19). pp. 3986–3996. 10.1182/blood-2012-05-433334 Retrieved from https://hdl.handle.net/10161/19327.

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Scholars@Duke

Xu-Monette

Zijun Yidan Xu-Monette

Assistant Professor in Pathology

My research efforts have been focused on identifying prognostic and therapeutic biomarkers in B-cell lymphoma. My research interests also include investigation of molecular and immune mechanisms underlying the poor clinical outcomes of lymphoma, the pathogenesis and evolution of drug resistant clones, and development of novel therapies for aggressive B-cell lymphoma.

Young

Ken H Young

Professor of Pathology

I am a clinically-oriented diagnostic physician with clinical expertise in the pathologic diagnosis of hematologic cancers including tumors of the bone marrow, lymphoid tissue, spleen and pre-malignant hematologic conditions. Another area of interest is blood cancer classification with molecular and genetic profiling. In the research program, we focus on molecular mechanisms of tumor progression, cell-of-origin, biomarkers, and novel therapeutic strategies in lymphoma, myeloma and leukemia. In addition to patient care and translational research, medical education and communication are also part of focus. I provide persistent support for the physician-scientist program and Blood Cancer Pathology program in the department and cancer center. Many residents, fellows, graduates and postdocs have worked and been trained in our program. We perform comprehensive clinical and research functions that include bone marrow, lymphoma pathology, clinical flow cytometry, cytogenetics, molecular diagnostics and outside services.

I am currently the director of hematopathology division that provides diagnostic consultation services and relevant specialized testing for patients with various types of acute and chronic leukemia, lymphoma and benign hematologic disorders. I am specialized in the diagnosis of hematological disorders, including acute and chronic leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, B and T-cell lymphomas, Hodgkin lymphoma, cutaneous and orbital lymphomas and benign bone marrow and lymph node disorders. 

Our clinical and research collaborative groups have been supported by various funding resources since 2006 and have published more than 300 original peer-reviewed articles and review articles, many in high- impact journals (Nature Clin Onc Rev, JCO, JAMA, Lancet, Blood, JHO, Leukemia and Clinical Cancer Research). The contributions to the hematology field include the development of novel diagnostic algorithms, molecular and genetic biomarkers for classification of blood cancer, lymphoid neoplasms and lymphoid diseases.


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