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.

Details

Title
Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma
Author
Bai, Baoyan 1   VIAFID ORCID Logo  ; Wise, Jillian F. 2 ; Vodák, Daniel 3 ; Nakken, Sigve 4   VIAFID ORCID Logo  ; Sharma, Ankush 5   VIAFID ORCID Logo  ; Blaker, Yngvild Nuvin 6 ; Brodtkorb, Marianne 7 ; Hilden, Vera 5 ; Trøen, Gunhild 8 ; Ren, Weicheng 9 ; Lorenz, Susanne 10 ; Lawrence, Michael S. 11 ; Myklebost, Ola 12   VIAFID ORCID Logo  ; Kimby, Eva 13   VIAFID ORCID Logo  ; Pan-Hammarström, Qiang 9   VIAFID ORCID Logo  ; Steen, Chloé B. 5 ; Meza-Zepeda, Leonardo A. 14 ; Beiske, Klaus 8 ; Smeland, Erlend B. 6 ; Hovig, Eivind 15   VIAFID ORCID Logo  ; Lingjærde, Ole Christian 16   VIAFID ORCID Logo  ; Holte, Harald 17   VIAFID ORCID Logo  ; Myklebust, June Helen 5   VIAFID ORCID Logo 

1  Oslo University Hospital, Department of Cancer Immunology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Akershus University Hospital, Department of Clinical Molecular Biology (EpiGen),, Lørenskog, Norway (GRID:grid.411279.8) (ISNI:0000 0000 9637 455X) 
2  Oslo University Hospital, Department of Cancer Immunology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.5510.1); Harvard Medical School, Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of Harvard and MIT, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
3  CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.66859.34); Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
4  CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.55325.34); Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); University of Oslo, Centre for Bioinformatics, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
5  Oslo University Hospital, Department of Cancer Immunology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); University of Oslo, Precision Immunotherapy Alliance, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
6  Oslo University Hospital, Department of Cancer Immunology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
7  University of Oslo, KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital, Department of Oncology, Division for Cancer Medicine, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
8  Oslo University Hospital, Department of Pathology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
9  Karolinska Institutet, Division of Immunology, Department of Medical Biochemistry and Biophysics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
10  CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.4714.6); Oslo University Hospital, Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
11  Harvard Medical School, Massachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of Harvard and MIT, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
12  CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.66859.34); Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Bergen, Department for Clinical Science, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443) 
13  Unit for Hematology and Department of Medicine at Karolinska Institutet, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
14  CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.5510.1); Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); Oslo University Hospital, Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
15  CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.5510.1); Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Centre for Bioinformatics, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
16  University of Oslo, KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); University of Oslo, Department of Informatics, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital, Department of Cancer Genetics, Institute for Cancer Research, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
17  University of Oslo, KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); CancerGenomics.no, Norwegian Cancer Genomics Consortium, Oslo, Norway (GRID:grid.5510.1); Oslo University Hospital, Department of Oncology, Division for Cancer Medicine, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
Pages
147
Publication year
2024
Publication date
Dec 2024
Publisher
Springer Nature B.V.
e-ISSN
20445385
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41408-024-01124-5
ProQuest document ID
3097624390
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.