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.
滤泡性淋巴瘤是B细胞非霍奇金淋巴瘤中最常见的惰性亚型。尽管治疗进展改善了患者总生存期，但早期复发或转化为侵袭性疾病仍与不良预后相关。为明确早期遗传学事件并追踪肿瘤克隆演化，我们对44例滤泡性淋巴瘤患者的94份纵向活检样本进行了多组学分析，其中22例发生转化（tFL），22例未转化仅复发（nFL）。深度全外显子测序证实表观遗传调控基因（CREBBP、KMT2D、EZH2、EP300）存在复发性突变，且nFL与tFL患者突变谱相似。通过计算纵向样本间的基因组距离，揭示出两个亚组均存在复杂的演化模式。研究发现CREBBP和KMT2D突变是病程早期发生的遗传学事件，其中CREBBP的KAT结构域突变病例具有较低的转化风险。12号和18号染色体增益（涉及TCF4）以及6q缺失被确定为早期且稳定的拷贝数变异。这类早期稳定遗传学事件的识别可能为疾病早期检测与监测提供新途径。整合分析显示，携带EZH2突变的肿瘤表现出包括组蛋白连接基因在内的多个组蛋白基因表达下调，这可能是导致滤泡性淋巴瘤表观遗传失调的重要因素。
Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma
肿瘤(癌症)患者之家