Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma,Blood Cancer Journal

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Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma
Blood Cancer Journal ( IF 12.9 ) Pub Date : 2024-08-27 , DOI: 10.1038/s41408-024-01124-5
Baoyan Bai _{1,

2,

3} , Jillian F Wise _{1,

2,

4,

5,

6} , Daniel Vodák _{4,

7} , Sigve Nakken _{4,

7,

8,

9} , Ankush Sharma _{1,

2,

10} , Yngvild Nuvin Blaker _{1,

2} , Marianne Brodtkorb _{2,

11} , Vera Hilden _{1,

2,

10} , Gunhild Trøen ₁₂ , Weicheng Ren ₁₃ , Susanne Lorenz _{4,

14} , Michael S Lawrence _{5,

6} , Ola Myklebost _{4,

7,

15} , Eva Kimby ₁₆ , Qiang Pan-Hammarström ₁₃ , Chloé B Steen _{1,

2,

10} , Leonardo A Meza-Zepeda _{4,

7,

14} , Klaus Beiske ₁₂ , Erlend B Smeland _{1,

2} , Eivind Hovig _{4,

7,

9} , Ole Christian Lingjærde _{2,

17,

18} , Harald Holte _{2,

4,

11} , June Helen Myklebust _{1,

2,

10}

Affiliation

Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Clinical Molecular Biology (EpiGen),, Akershus University Hospital, Lørenskog, Norway.
Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway.
Massachusetts General Hospital Cancer Center and Department of Pathology, Harvard Medical School, Charlestown, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Centre for Bioinformatics, University of Oslo, Oslo, Norway.
Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway.
Department of Oncology, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway.
Department of Pathology, Oslo University Hospital, Oslo, Norway.
Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Department for Clinical Science, University of Bergen, Bergen, Norway.
Unit for Hematology and Department of Medicine at Karolinska Institutet, Huddinge, Stockholm, Sweden.
Department of Informatics, University of Oslo, Oslo, Norway.
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

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.

中文翻译：

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惰性类型。治疗的进步提高了总生存期，但早期复发或转变为侵袭性疾病与较差的结局相关。为了识别早期遗传事件并追踪肿瘤克隆进化，我们对 44 例 FL 患者的 94 例纵向活检进行了多组学分析;22 例转化（tFL）和 22 例复发无转化（nFL）。深度全外显子组测序证实了编码表观遗传调节因子（CREBBP 、 KMT2D 、 EZH2 、 EP300） 的基因的复发性突变，在 nFL 和 tFL 患者中具有相似的突变景观。纵向样本之间基因组距离的计算揭示了两个亚组中复杂的进化模式。CREBBP 和 KMT2D 突变被确定为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低。12 号和 18 号染色体（TCF4）的增加和 6q 的缺失被确定为早期和稳定的拷贝数改变。识别这种早期和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。整合分析显示，具有 EZH2 突变的肿瘤表现出许多组蛋白基因的基因表达降低，包括组蛋白接头基因。这可能导致 FL 中的表观遗传失调。

更新日期：2024-08-28

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