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Last Updated: 06/26/15

Molecular Diagnosis and Prognosis in Aggressive Lymphoma

Lisa M. Rimsza, MD
University of Arizona, Tucson, AZ

Dr. Rimsza’s program, as a component of the Lymphoma and Leukemia Molecular Profiling Project (LLMPP), will design and validate multi-analyte diagnostic and prognostic assays to differentiate aggressive B-cell non-Hodgkin’s lymphoma into prognostic groups. The tissue samples will be formalin-fixed and paraffin-embedded (FFPE) and the data generated will be submitted for regulatory review with the intention of establishing a highly accurate standardized diagnostic test with prognostic indicators for widespread clinical use. The ability to distinguish prognostic subgroups will enable the development of therapeutic agents to improve outcomes for patients with the most aggressive forms of this disease.

Collaborators:

  • This international project team includes investigators from the University of Arizona, National Cancer Institute, University of Rochester Medical Center, Oregon Health and Science University, Cleveland Clinic, Fred Hutchinson Cancer Research Center, City of Hope, BC Cancer Agency (British Columbia, Canada), Oslo University Hospital, the University of Wurzburg, Robert-Bosch-Hospital Stuttgart (Germany), Clinic Corporacio Sanitaria (Spain), Institut Catala d’Oncologia (France), Affymetrix, High Throughput Genomics, Inc., and Nanostring Technologies.
  • The earlier studies that produced the algorithms of interest to this project were done on frozen tissues provided by 8 LLMPP tissue banks. The same banks will provide, as available, matched FFPE specimens for this study.

Projects:

  • Develop a multi-analyte diagnostic and prognostic test for aggressive B cell lymphomas using FFPE lymphoma biopsies

Publications:

Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue.

Authors: Scott DW, Wright GW, Williams PM, Lih CJ, Walsh W, Jaffe ES, Rosenwald A, Campo E, Chan WC, Connors JM, Smeland EB, Mottok A, Braziel RM, Ott G, Delabie J, Tubbs RR, Cook JR, Weisenburger DD, Greiner TC, Glinsmann-Gibson BJ, Fu K, Staudt LM, Gascoyne RD, Rimsza LM

Source: Blood. 2014 Feb 20;123(8):1214-7. doi: 10.1182/blood-2013-11-536433. Epub 2014 Jan 7.

Abstract: The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B cell-like or activated B cell-like groups. The Lymphoma/Leukemia Molecular Profiling Project's Lymph2Cx assay is a parsimonious digital gene expression (NanoString)-based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET). The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort, the assay was accurate, with only 1 case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turnaround time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management.

BCL2 antibodies targeted at different epitopes detect varying levels of protein expression and correlate with frequent gene amplification in diffuse large B-cell lymphoma.

Authors: Kendrick, S. L., L. Redd, et al. (2014)

Source: Hum Pathol 45(10): 2144-2153.

Abstract: Patients with aggressive, BCL2 protein-positive (+) diffuse large B-cell lymphoma (DLBCL) often experience rapid disease progression that is refractory to standard therapy. However, there is potential for false-negative staining of BCL2 using the standard monoclonal mouse 124 antibody that hinders the identification of these high-risk DLBCL patients. Herein, we compare 2 alternative rabbit monoclonal antibodies (E17 and SP66) to the 124 clone in staining for BCL2 in formalin-fixed, paraffin-embedded DLBCL tissues. Overall, in 2 independent DLBCL cohorts, E17 and SP66 detected BCL2 expression more frequently than 124. In the context of MYC expression, cases identified as BCL2 (+) with SP66 demonstrated the strongest correlation with worse overall survival. The 124 clone failed to detect BCL2 expression in the majority of translocation (+), amplification (+), and activated B-cell DLBCL cases in which high levels of BCL2 protein are expected. Using dual in situ hybridization as a new tool to detect BCL2 translocation and amplification, we observed similar results as previously reported for fluorescence in situ hybridization for translocation but a higher amplification frequency, indicating that BCL2 amplification may be underreported in DLBCL. Among the discrepant cases, phosphorylation of BCL2 at T69 and/or S70 was more common than in the concordant cases and may contribute to the 124 false negatives, in addition to previously associated mutations within the epitope region. The accurate detection of BCL2 expression is important in the prognosis and treatment of DLBCL particularly with new anti-BCL2 therapies.