A prognostic signature based on ectopic reactivation of eight tissue-specific genes in Diffuse Large B Cell Lymphoma.

Diffuse Large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in the Western world. First-line immunochemotherapy fails in approximately 30-40% of patients, with refractory and relapse patients presenting a dismal prognosis. Currently, these high-risk patients cannot be accurately identified at diagnosis. Using statistical modeling and machine learning approaches applied to large public DLBCL datasets, we identified a novel predictive signature based on the reactivation of eight normally silent tissue-dependent genes associated with survival. We then developed a multiplex RT-MLPseq based assay, compatible with formalin-fixed paraffin-embedded (FFPE) samples and transferable into routine clinical practice, enabling analysis of expression of these eight genes and validated their prognosis impact in an independent real-life cohort. This signature could be integrated with current prognostic indices and molecular classifications to improve patient stratification and guide treatment selection toward a personalized theragnostic approach, thereby enhancing management of non-responder patients. Data Sharing StatementFor access to original data, please contact: anouk.emadali@univ-grenoble-alpes.fr Key points- Ectopic activation of 8 tissue-specific genes defines a robust prognostic signature for survival stratification in DLBCL patients - A FFPE-compatible RT-MLPseq assay enables clinical use and improves risk stratification beyond IPI and COO, especially in high-risk patients