Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma

• Published in: Signal transduction and targeted therapy Vol. 8; no. 1; p. 145
• Main Authors: Shen, Rong, Fu, Di, Dong, Lei, Zhang, Mu-Chen, Shi, Qing, Shi, Zi-Yang, Cheng, Shu, Wang, Li, Xu, Peng-Peng, Zhao, Wei-Li
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.04.2023; Nature Publishing Group UK
• Subjects: 1-Phosphatidylinositol 3-kinase; Algorithms; B-cell lymphoma; Bcl-6 protein; BTG2 protein; Butyrate Response Factor 1 - genetics; CD70 antigen; CIITA protein; Fluorescence in situ hybridization; Genomes; Humans; Immediate-Early Proteins - genetics; Immediate-Early Proteins - therapeutic use; In Situ Hybridization, Fluorescence; Interferon regulatory factor 4; Interleukin-1 Receptor-Like 1 Protein - genetics; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Mutation; Myc protein; MyD88 protein; NF-kappa B - genetics; NF-κB protein; Notch1 protein; p53 Protein; Prognosis; Proto-Oncogene Proteins c-bcl-2 - genetics; Stat3 protein; Stat6 protein; Tumor Microenvironment; Tumor Suppressor Proteins - genetics
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-023-01358-y

Genetic classification helps to disclose molecular heterogeneity and therapeutic implications in diffuse large B-cell lymphoma (DLBCL). Using whole exome/genome sequencing, RNA-sequencing, and fluorescence in situ hybridization in 337 newly diagnosed DLBCL patients, we established a simplified 38-gene algorithm (termed 'LymphPlex') based on the information on mutations of 35 genes and rearrangements of three genes (BCL2, BCL6, and MYC), identifying seven distinct genetic subtypes: TP53 (TP53 mutations), MCD-like (MYD88, CD79B, PIM1, MPEG1, BTG1, TBL1XR1, PRDM1, IRF4 mutations), BN2-like (BCL6 fusion, NOTCH2, CD70, DTX1, BTG2, TNFAIP3, CCND3 mutations), N1-like (NOTCH1 mutations), EZB-like (BCL2 fusion, EZH2, TNFRSF14, KMT2D, B2M, FAS, CREBBP, ARID1A, EP300, CIITA, STAT6, GNA13 mutations, with or without MYC rearrangement), and ST2-like (SGK1, TET2, SOCS1, DDX3X, ZFP36L1, DUSP2, STAT3, IRF8 mutations). Extended validation of 1001 DLBCL patients revealed clinical relevance and biological signature of each genetic subtype. TP53 subtype showed poor prognosis, characterized by p53 signaling dysregulation, immune deficiency, and PI3K activation. MCD-like subtype was associated with poor prognosis, activated B-cell (ABC) origin, BCL2/MYC double-expression, and NF-κB activation. BN2-like subtype showed favorable outcome within ABC-DLBCL and featured with NF-κB activation. N1-like and EZB-like subtypes were predominated by ABC-DLBCL and germinal center B-cell (GCB)-DLBCL, respectively. EZB-like-MYC subtype was characterized by an immunosuppressive tumor microenvironment, while EZB-like-MYC subtype by NOTCH activation. ST2-like subtype showed favorable outcome within GCB-DLBCL and featured with stromal-1 modulation. Genetic subtype-guided targeted agents achieved encouraging clinical response when combined with immunochemotherapy. Collectively, LymphPlex provided high efficacy and feasibility, representing a step forward to the mechanism-based targeted therapy in DLBCL.