Molecular diagnostic and prognostic signatures for PTCL

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Abstract Peripheral T-cell lymphomas (PTCL) represent approximately 10-12% of all NHL in the western world and generally exhibit poor prognosis with standard chemotherapy. Another significant challenge is that using current diagnostic approaches, approximately 30-50% of PTCL cases cannot be assigned to a specific entity and are categorized as PTCL-not otherwise specified (PTCL-NOS). Of the more common PTCL entities recognized by WHO classification, we have defined robust molecular gene expression signatures that can differentiate the five PTCLs entities: angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase positive anaplastic large-cell lymphoma (ALK(+)ALCL), ALK-negative anaplastic large-cell lymphoma (ALK(-)ALCL), adult T-cell leukemia/lymphoma (ATLL), and extranodal natural killer/T-cell lymphoma (ENKTCL). PTCL-NOS can now be separated into two distinct molecular subgroups (the TBX21 and GATA3 subgroups). A prognostic model for AITL has also been developed. Overall, these represent more than 80% of all the PTCL. The aim of this proposal is to consolidate these diagnostic and prognostic signatures into a single technology platform that can be applied to formalin fixed, paraffin embedded tissues (FFPET) to improve standardization and accuracy of PTCL diagnosis. This platform will be applicable to not only routine clinical applications, but will help to stratify patients in prospective clinical trials for new therapeutic agents. We will validate these signatures in a CLIA setting at two different locations for reproducibility and will subsequently evaluate specimens from six clinical trials. Clinical samples and data essential to develop these assays will be obtained from the two major consortiums: the International PTCL Project (IP-PTCL) and the Lymphoma and Leukemia Molecular Profiling Project (LLMPP), which had provided specimens and clinical data for the GEP study. Additional institutions will participate to provide new cases for validation studies. We are uniquely positioned to accomplish this work by having derived the “gold standard” diagnostic and prognostic signatures of these lymphomas, as well as having matching fresh frozen tissue and FFPET blocks. Our group has used a similar approach to develop the “Lymph2Cx” assay for a robust distinction between the GCB and ABC subtype of diffuse large B-cell lymphoma.