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DLBCL patients included 075-GOELAMS trial or 075-like patient.

Blood donors from the EFS (French Blood Bank) of Rennes.

septic patients included at the Rennes University Hospital.

DLBCL patients from the 075 GOELAMS study in completed remission.

Thierry Fest, MD

Diffuse Large B-cell Lymphoma (DLBCL) is the most frequent high grade lymphoma in adults. Although immunotherapy has improved its prognosis, DLBCL is a heterogeneous disease with patients exhibiting a wide range of outcomes with a 5-year overall survival ranging between 55 to 94% depending of the International Prognostic Index factor. Diagnostic and prognostic biomarkers are mandatory to optimize treatment. Transcriptomics has been used to detect such new biomarkers using microarrays analyses applied to RNA collected from total tumor tissues or cell extracts. Molecular prognostic factors have been thoroughly studied in DLBCL tumor tissues. However, it is a big challenge to obtain transcriptomic-qualified tumor samples in a multicentric and prospective clinical trial. Coordinating nvestigator hypothesized that blood may be a deep source of native and secreted analytes and therefore carries transcriptomic signatures related to DLBCL and its prognosis. This project is organized in the extension of the GOELAMS-075 clinical trial which concerns aggressive DLBCL.

Two complementary approaches will be followed, one at the transcriptomic level for confirmation of diagnostic biomarkers and to assess for predictive biomarkers. The other one concern biologic studies to validate our biomarkers at the tissue level. Our project will be organized around 4 workpackages (WP), each of them includes tasks with a specific schedule \& predefined deliverables. The first one concerns the general management, data warehouse, collections and different administrative and preanalytic issues. The 3 other WPs are scientific. We are first going to validate a 30-gene list, candidate diagnostic biomarkers, by qRT-PCR on: \*) an independent set of DLBCLs compared to matched healthy blood donors (sensitivity assessment) and, \*\*) on a series of low tumor burden DLBCLs, mantle cell lymphomas and non-malignant inflammatory disease constituted by patients with a septic shock (specificity assessment). All this latter collections are already available and ready to use. Secondly, we will complete our series of 89 hybridized patients on AFFY WholeExon microarrays by 60 supplementary and available samples in order to assess for molecular predictor of patient outcome. This question will be address based on the 3-year and 5-year as well, EFS (Event Free Survivor). All the clinical data are available through the GOELAMS eCRF. Since we dispose of a 31 probesets, 30 single genes, signature for the DLBCL diagnosis that involves 9 genes related to the myeloid compartment including 6 genes involved directly or not to the Myeloid-Derived Cell Suppression (MDSC) process, 20 genes described in the context of the cancer and, 11 genes connected to endothelial cells, we decided to explore by flow cytometry blood circulating cells. We will look for myeloid populations \& subpopulations, endothelial cells and microparticles. The goal is the identification of specific MDSC perturbations, angiogenic abnormalities and functional impacts on the immune response in the context of the cancer.

We expect by our work to drive both basic science and clinical implications. On the scientific level, blood carries molecular and cellular components involved in tumor-host interactions. Our project should bring a deeper understanding in the immunological response that takes place in the blood compartment. This immunological response will be characterized on a molecular, cellular and functional level. On a clinical point of view, it may bring a new prognostic model in DLBCL. As blood is easily accessible, we expect it to be easily implemented in clinical practice and to allow the design of new clinical trials stratified on tumor biology features. It may also become a new way to monitor DLBCL's response to treatment. Furthermore, this project will provide a large amount of molecular data that can be easily connected with other ongoing GOELAMS studies. Valorisation of our findings will also be serious issue since our project is highly original and valuable.

For this study, 4 newly included cohorts are necesseray :

* 100 new DLBCL patients are necessary. The blood will be taken at the diagnosis for DLBCL patients included 075-GOELAMS trial or 075-like patient.
* 100 healthy blood donors. This cohort of matched for sex \& gender will be constituted at the EFS (French Blood Bank) of Rennes.
* 100 septic patients included at the Rennes University Hospital.
* 100 075-like DLBCL patients in completed remission.

This project will also used already available blood collections: 2) Mantle cell lymphoma, 3) localized DLBCL and septic shock. Paraffin blocks of patient 075-trial DLBCLs are in the GOELAMSthèque bank localized in the Pathology Department Hôtel Dieu, Paris supervised by Pr Diane Damotte. Tissue Microarrays and complete paraffin blocks as well as some -80° tumors are already available.

Assessment of Blood Biomarkers by DNA Microarrays in Patients With Aggressive Lymphoma BMS_LyTrans

Assessment of Biomarkers Initially Identified in Whole Blood by DNA Microarrays in Patients With Aggressive Lymphoma BMS_LyTrans

In this project we propose two complementary approaches with a first one orientated to the continuum of our current findings based on genes differentially expressed in blood between DLBCL patients and healthy people and a second one which takes in account the power and originality of our 075 GOELAMS cohort and will be focused on the research of predictive signatures of the DLBCL. We will go beyond the sole transcriptomic approach and also look for relevant cell biology clues.

Sensitivity \& specificity of the identified molecular signature in the DLBCL

Identify a prognostic whole blood RNA signature related to aggressive DLBCL

Proportion and phenotypic characteristics of circulating cells expressing the previously identified biomarkers at the time of diagnosis of DLBCL

Immune functions of these circulating cells expressing the previously identified biomarkers at the time of diagnosis of DLBCL

Spots Global Cancer Trial Database for secondary lymphoid organs