Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany.
Hematopathology Unit, Hospital Clínic de Barcelona, Barcelona, Spain.
Blood Adv. 2022 Apr 12;6(7):2361-2372. doi: 10.1182/bloodadvances.2021006034.
Diffuse large B-cell lymphoma (DLBCL) with aberrant coexpression of CD10+BCL6+MUM1+ (DLBCL-AE), classified as germinal center B cell (GCB) type by the Hans algorithm (HA), was genetically characterized. To capture the complexity of DLBCL-AE, we used an integrated approach that included gene expression profiling (GEP), fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. According to GEP, 32/54 (59%) cases were classified as GCB-DLBCL, 16/54 (30%) as activated B-cell (ABC) DLBCL, and 6/54 (11%) as unclassifiable. The discrepancy between HA and GEP was 41%. Three genetic subgroups were identified. Group 1 included 13/50 (26%) cases without translocations and mainly showing and ABC/MCD molecular profile. Group 2 comprised 11/50 (22%) cases with IRF4 alterations (DLBCL-IRF4), frequent mutations in IRF4 (82%) and NF-κB pathway genes (MYD88, CARD11, and CD79B), and losses of 17p13.2. Five cases each were classified as GCB- or ABC-type. Group 3 included 26/50 (52%) cases with 1 or several translocations in BCL2/BCL6/MYC/IGH, and GCB/EZB molecular profile predominated. Two cases in this latter group showed complex BCL2/BCL6/IRF4 translocations. DLBCL-IRF4 in adults showed a similar copy number profile and shared recurrent CARD11 and CD79B mutations when compared with LBCL-IRF4 in the pediatric population. However, adult cases showed higher genetic complexity, higher mutational load with frequent MYD88 and KMT2D mutations, and more ABC GEP. IRF4 mutations were identified only in IRF4-rearranged cases, indicating its potential use in the diagnostic setting. In conclusion, DLBCL-AE is genetically heterogeneous and enriched in cases with IRF4 alterations. DLBCL-IRF4 in adults has many similarities to the pediatric counterpart.
弥漫性大 B 细胞淋巴瘤（DLBCL）表现为 CD10+BCL6+MUM1+异常共表达（DLBCL-AE），按照 Hans 算法（HA）分类为生发中心 B 细胞（GCB）型。我们对这种具有遗传特征的 DLBCL-AE 进行了研究。为了捕捉 DLBCL-AE 的复杂性，我们采用了一种综合方法，包括基因表达谱分析（GEP）、荧光原位杂交、靶向基因测序和拷贝数（CN）阵列。根据 GEP，54 例中有 32 例（59%）被归类为 GCB-DLBCL，16 例（30%）为激活 B 细胞（ABC）DLBCL，6 例（11%）为无法分类。HA 和 GEP 之间的差异为 41%。确定了三个遗传亚组。第 1 组包括 50 例中的 13 例（26%），无易位，主要表现为 ABC/MCD 分子特征。第 2 组包括 50 例中的 11 例（22%），具有 IRF4 改变（DLBCL-IRF4），IRF4 基因（82%）和 NF-κB 通路基因（MYD88、CARD11 和 CD79B）频繁突变，17p13.2 缺失。5 例为 GCB 或 ABC 型。第 3 组包括 50 例中的 26 例（52%），1 个或多个易位发生在 BCL2/BCL6/MYC/IGH 中，GCB/EZB 分子特征为主。该组中有两个病例表现出复杂的 BCL2/BCL6/IRF4 易位。与儿科人群中的 LBCL-IRF4 相比，成人的 DLBCL-IRF4 具有相似的拷贝数谱，并共享反复出现的 CARD11 和 CD79B 突变。然而，成人病例的遗传复杂性更高，突变负荷更高，常伴有 MYD88 和 KMT2D 突变，GEP 更倾向于 ABC 型。IRF4 突变仅在 IRF4 重排的病例中被识别，表明其在诊断中的潜在用途。总之，DLBCL-AE 在遗传上是异质性的，并且富含具有 IRF4 改变的病例。成人的 DLBCL-IRF4 与儿科的相似之处很多。
