Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma.

IF 12.9 1区医学 Q1 HEMATOLOGY

Blood Cancer Journal Pub Date : 2024-08-27 DOI:10.1038/s41408-024-01124-5

Baoyan Bai, Jillian F Wise, Daniel Vodák, Sigve Nakken, Ankush Sharma, Yngvild Nuvin Blaker, Marianne Brodtkorb, Vera Hilden, Gunhild Trøen, Weicheng Ren, Susanne Lorenz, Michael S Lawrence, Ola Myklebost, Eva Kimby, Qiang Pan-Hammarström, Chloé B Steen, Leonardo A Meza-Zepeda, Klaus Beiske, Erlend B Smeland, Eivind Hovig, Ole Christian Lingjærde, Harald Holte, June Helen Myklebust

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Abstract

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.

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纵向样本的多组学分析揭示了滤泡性淋巴瘤的早期基因组变化。

滤泡性淋巴瘤（FL）是B细胞非霍奇金淋巴瘤中最常见的隐匿型。治疗方面的进步提高了患者的总体生存率，但早期复发或向侵袭性疾病转化与较差的预后有关。为了确定早期遗传事件并追踪肿瘤克隆演变，我们对44例FL患者的94例纵向活检进行了多组学分析，其中22例为转化型（tFL），22例为复发但未转化型（nFL）。深度全外显子组测序证实，编码表观遗传调控因子（CREBBP、KMT2D、EZH2、EP300）的基因存在复发性突变，nFL和tFL患者的突变情况相似。计算纵向样本之间的基因组距离发现，这两个亚组都存在复杂的进化模式。CREBBP和KMT2D突变被认为是病程早期发生的遗传事件，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）的增益以及6q的缺失被确定为早期和稳定的拷贝数改变。识别这些早期和稳定的基因事件可为早期疾病检测和疾病监测提供机会。整合分析显示，EZH2突变的肿瘤表现出许多组蛋白基因（包括组蛋白连接子基因）的基因表达减少。这可能是前列腺癌表观遗传失调的原因之一。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Blood Cancer Journal ONCOLOGY-

CiteScore

16.70

自引率

2.30%

发文量

153

审稿时长

>12 weeks

期刊介绍： Blood Cancer Journal is dedicated to publishing high-quality articles related to hematologic malignancies and related disorders. The journal welcomes submissions of original research, reviews, guidelines, and letters that are deemed to have a significant impact in the field. While the journal covers a wide range of topics, it particularly focuses on areas such as: Preclinical studies of new compounds, especially those that provide mechanistic insights Clinical trials and observations Reviews related to new drugs and current management of hematologic malignancies Novel observations related to new mutations, molecular pathways, and tumor genomics Blood Cancer Journal offers a forum for expedited publication of novel observations regarding new mutations or altered pathways.