滤泡性淋巴瘤 (FL) 是最常见的惰性 B 细胞非霍奇金淋巴瘤类型。治疗的进步提高了总体生存率，但早期复发或转化为侵袭性疾病与较差的结果相关。为了识别早期遗传事件并追踪肿瘤克隆进化，我们对 44 名 FL 患者的 94 份纵向活检进行了多组学分析； 22 例发生转化 (tFL)，22 例复发但未发生转化 (nFL)。深度全外显子组测序证实编码表观遗传调节因子（CREBBP、KMT2D、EZH2、EP300）的基因反复发生突变，nFL 和 tFL 患者的突变情况相似。纵向样本之间基因组距离的计算揭示了两个亚群的复杂进化模式。 CREBBP 和 KMT2D 突变被确定为在病程早期发生的遗传事件，并且 CREBBP KAT 结构域突变的病例转化风险较低。 12 号和 18 号染色体 (TCF4) 的增加以及 6q 的丢失被确定为早期且稳定的拷贝数改变。识别此类早期且稳定的遗传事件可能为早期疾病检测和疾病监测提供机会。综合分析显示，具有 EZH2 突变的肿瘤表现出许多组蛋白基因（包括组蛋白接头基因）的基因表达降低。这可能会导致 FL 的表观遗传失调。© 2024。作者。

Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.© 2024. The Author(s).