与脾边缘区淋巴瘤（SMZL）转化（SMZL-T）相关的遗传机制尚不清楚。我们研究了41例最终经历大B细胞淋巴瘤转化的SMZL患者。肿瘤材料仅在诊断时（9例患者）、诊断和转化时（18例患者）以及仅在转化时（14例患者）获得。样本分为两组：i）诊断时（SMZL，n=27个样本），和ii）转化时（SMZL-T，n=32个样本）。使用拷贝数组和下一代测序自定义面板，我们确定了SMZL-T中的主要基因组变化涉及TNFAIP3、KMT2D、TP53、ARID1A、KLF2、1q增益和9p21.3（CDKN2A/B）和7q31-q32的失衡。与SMZL相比，SMZL-T具有更高的基因组复杂性和TNFAIP3、TP53突变、9p21.3（CDKN2A/B）缺失和6p增益的更高发生率。SMZL和SMZL-T克隆体均由共同变异的前体细胞产生的分歧演化而来，在几乎所有可评估的病例中（12/13, 92%），都获得了不同的基因变异。在一位患者的诊断和转化样本中使用全基因组测序，我们观察到SMZL-T样本携带的基因组畸变比诊断样本更多，发现了存在于两个样本中的t(14；19)(q32；q13)易位，并检测到由于染色体断裂（chromothripsis）导致的B2M差错删除在转化时获得。生存分析表明，KLF2突变、复杂染色体核型和转化时的国际预后指数预测转化后生存较短（P=0.001、P=0.042和P=0.007，分别）。总之，与SMZL相比，SMZL-T表现出更高的基因组复杂性和特有的基因组变异，这些变异可能是转化事件的关键因素。 版权所有（C）2023美国血液学会。

The genetic mechanisms associated with splenic marginal zone lymphoma transformation (SMZL-T) are not well defined. We studied 41 SMZL patients that eventually underwent large B-cell lymphoma transformation. Tumor material was obtained only at diagnosis (9 patients), at diagnosis and transformation (18 patients), and only at transformation (14 patients). Samples were categorized in two groups: i) at diagnosis (SMZL, n=27 samples), and ii) at transformation (SMZL-T, n=32 samples). Using copy number arrays and a next-generation sequencing custom panel, we identified that the main genomic alterations in SMZL-T involved TNFAIP3, KMT2D, TP53, ARID1A, KLF2, 1q gains and losses of 9p21.3 (CDKN2A/B) and 7q31-q32. Compared with SMZL, SMZL-T had higher genomic complexity, and higher incidence of TNFAIP3 and TP53 alterations, 9p21.3 (CDKN2A/B) losses and 6p gains. SMZL and SMZL-T clones arose by divergent evolution from a common altered precursor cell which acquired different genetic alterations in virtually all evaluable cases (12/13, 92%). Using whole genome sequencing from diagnostic and transformation samples in one patient, we observed that the SMZL-T sample carried more genomic aberrations than the diagnostic sample, identified a translocation t(14;19)(q32;q13) present in both samples, and detected a focal B2M deletion due to chromothripsis acquired at transformation. Survival analysis showed that KLF2 mutations, complex karyotype and international prognostic index at transformation predicted for a shorter survival from transformation (P=0.001, P=0.042, and P=0.007, respectively). In summary, SMZL-T are characterized by higher genomic complexity than SMZL, and characteristic genomic alterations that could represent key players in the transformation event.Copyright © 2023 American Society of Hematology.