Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics; National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Signal Transduct Target Ther. 2023 Apr 10;8(1):145. 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.
遗传分类有助于揭示弥漫性大 B 细胞淋巴瘤（DLBCL）的分子异质性和治疗意义。通过对 337 例新诊断的 DLBCL 患者进行全外显子/基因组测序、RNA 测序和荧光原位杂交，我们基于 35 个基因突变和 3 个基因（BCL2、BCL6 和 MYC）重排的信息，建立了一个简化的 38 基因算法（称为“LymphPlex”），确定了 7 种不同的遗传亚型：TP53（TP53 突变）、MCD 样（MYD88、CD79B、PIM1、MPEG1、BTG1、TBL1XR1、PRDM1、IRF4 突变）、BN2 样（BCL6 融合、NOTCH2、CD70、DTX1、BTG2、TNFAIP3、CCND3 突变）、N1 样（NOTCH1 突变）、EZB 样（BCL2 融合、EZH2、TNFRSF14、KMT2D、B2M、FAS、CREBBP、ARID1A、EP300、CIITA、STAT6、GNA13 突变，伴有或不伴有 MYC 重排）和 ST2 样（SGK1、TET2、SOCS1、DDX3X、ZFP36L1、DUSP2、STAT3、IRF8 突变）。对 1001 例 DLBCL 患者的扩展验证揭示了每个遗传亚型的临床相关性和生物学特征。TP53 亚型预后不良，表现为 p53 信号通路失调、免疫缺陷和 PI3K 激活。MCD 样亚型与预后不良相关，起源于激活的 B 细胞（ABC），BCL2/MYC 双表达，NF-κB 激活。BN2 样亚型在 ABC-DLBCL 中预后良好，特征为 NF-κB 激活。N1 样和 EZB 样亚型分别以 ABC-DLBCL 和生发中心 B 细胞（GCB）-DLBCL 为主。EZB 样-MYC 亚型的特点是免疫抑制性肿瘤微环境，而 EZB 样-MYC 亚型的特点是 NOTCH 激活。ST2 样亚型在 GCB-DLBCL 中预后良好，特征为基质-1 调节。遗传亚型指导的靶向药物与免疫化疗联合应用时，可获得令人鼓舞的临床反应。总的来说，LymphPlex 具有高疗效和可行性，代表着 DLBCL 向基于机制的靶向治疗迈出了一步。
