Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival
Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic neoplasm that affects humans as well as dogs. While previous studies on canine DLBCL (cDLBCL) have significantly advanced our understanding of the disease, the majority of this research has relied on whole-exome sequencing...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-89245-0 |
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| author | Anna Darlene van der Heiden Raphaela Pensch Sophie Agger Heather L. Gardner William Hendricks Victoria Zismann Shukmei Wong Natalia Briones Bryce Turner Karin Forsberg-Nilsson Cheryl London Kerstin Lindblad-Toh Maja Louise Arendt |
| author_facet | Anna Darlene van der Heiden Raphaela Pensch Sophie Agger Heather L. Gardner William Hendricks Victoria Zismann Shukmei Wong Natalia Briones Bryce Turner Karin Forsberg-Nilsson Cheryl London Kerstin Lindblad-Toh Maja Louise Arendt |
| author_sort | Anna Darlene van der Heiden |
| collection | DOAJ |
| description | Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic neoplasm that affects humans as well as dogs. While previous studies on canine DLBCL (cDLBCL) have significantly advanced our understanding of the disease, the majority of this research has relied on whole-exome sequencing, which is limited in its ability to detect copy number aberrations and other genomic changes beyond coding regions. Furthermore, many of these studies lack sufficient clinical follow-up data, making it difficult to draw meaningful associations between genetic variants and patient outcomes. Our study aimed to characterize the mutational landscape of cDLBCL using whole-genome sequencing of matched tumor-normal samples obtained from a cohort of 43 dogs previously enrolled in a clinical trial for which longitudinal follow-up was available. We focused on identifying genes that were significantly or recurrently mutated with coding point mutations, copy number aberrations, and their associations with patient outcomes. We identified 26 recurrently mutated genes, 18 copy number gains, and 8 copy number losses. Consistent with prior studies, the most commonly mutated genes included TRAF3, FBXW7, POT1, TP53, SETD2, DDX3X and TBL1XR1. The most prominent copy number gain occurred on chromosome 13, overlapping key oncogenes such as MYC and KIT, while the most frequent deletion was a focal loss on chromosome 26, encompassing IGL, PRAME, GNAZ, RAB36, RSPH14, and ZNF280B. Notably, our set of recurrently mutated genes was significantly enriched with genes involved in epigenetic regulation. In particular, we identified hotspot mutations in two histone genes, H3C8, and LOC119877878, resulting in H3K27M alterations predicted to dysregulate gene expression. Finally, a survival analysis revealed that H3K27M mutations in H3C8 were associated with increased hazard ratios for progression-free survival. No copy number aberrations were associated with survival. These findings underscore the critical role of epigenetic dysregulation in cDLBCL and affirm the dog as a relevant large animal model for interrogating the biological activity of novel histone-modifying treatment strategies. |
| format | Article |
| id | doaj-art-a22fe5fbf8e64140bb290d12e32e11ed |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-a22fe5fbf8e64140bb290d12e32e11ed2025-02-09T12:30:21ZengNature PortfolioScientific Reports2045-23222025-02-0115111410.1038/s41598-025-89245-0Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survivalAnna Darlene van der Heiden0Raphaela Pensch1Sophie Agger2Heather L. Gardner3William Hendricks4Victoria Zismann5Shukmei Wong6Natalia Briones7Bryce Turner8Karin Forsberg-Nilsson9Cheryl London10Kerstin Lindblad-Toh11Maja Louise Arendt12Department of Medical Biochemistry and Microbiology, Uppsala UniversityDepartment of Medical Biochemistry and Microbiology, Uppsala UniversityDepartment of Veterinary Clinical Sciences, University of CopenhagenCummings School of Veterinary Medicine, Tufts UniversityDivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen)Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen)Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen)Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen)Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen)SciLifeLab, Uppsala UniversityCummings School of Veterinary Medicine, Tufts UniversityDepartment of Medical Biochemistry and Microbiology, Uppsala UniversityDepartment of Medical Biochemistry and Microbiology, Uppsala UniversityAbstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic neoplasm that affects humans as well as dogs. While previous studies on canine DLBCL (cDLBCL) have significantly advanced our understanding of the disease, the majority of this research has relied on whole-exome sequencing, which is limited in its ability to detect copy number aberrations and other genomic changes beyond coding regions. Furthermore, many of these studies lack sufficient clinical follow-up data, making it difficult to draw meaningful associations between genetic variants and patient outcomes. Our study aimed to characterize the mutational landscape of cDLBCL using whole-genome sequencing of matched tumor-normal samples obtained from a cohort of 43 dogs previously enrolled in a clinical trial for which longitudinal follow-up was available. We focused on identifying genes that were significantly or recurrently mutated with coding point mutations, copy number aberrations, and their associations with patient outcomes. We identified 26 recurrently mutated genes, 18 copy number gains, and 8 copy number losses. Consistent with prior studies, the most commonly mutated genes included TRAF3, FBXW7, POT1, TP53, SETD2, DDX3X and TBL1XR1. The most prominent copy number gain occurred on chromosome 13, overlapping key oncogenes such as MYC and KIT, while the most frequent deletion was a focal loss on chromosome 26, encompassing IGL, PRAME, GNAZ, RAB36, RSPH14, and ZNF280B. Notably, our set of recurrently mutated genes was significantly enriched with genes involved in epigenetic regulation. In particular, we identified hotspot mutations in two histone genes, H3C8, and LOC119877878, resulting in H3K27M alterations predicted to dysregulate gene expression. Finally, a survival analysis revealed that H3K27M mutations in H3C8 were associated with increased hazard ratios for progression-free survival. No copy number aberrations were associated with survival. These findings underscore the critical role of epigenetic dysregulation in cDLBCL and affirm the dog as a relevant large animal model for interrogating the biological activity of novel histone-modifying treatment strategies.https://doi.org/10.1038/s41598-025-89245-0DogCanineDiffuse large B-cell lymphomaPrognosisGenomicsOncogenetics |
| spellingShingle | Anna Darlene van der Heiden Raphaela Pensch Sophie Agger Heather L. Gardner William Hendricks Victoria Zismann Shukmei Wong Natalia Briones Bryce Turner Karin Forsberg-Nilsson Cheryl London Kerstin Lindblad-Toh Maja Louise Arendt Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival Scientific Reports Dog Canine Diffuse large B-cell lymphoma Prognosis Genomics Oncogenetics |
| title | Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival |
| title_full | Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival |
| title_fullStr | Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival |
| title_full_unstemmed | Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival |
| title_short | Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival |
| title_sort | characterization of the genomic landscape of canine diffuse large b cell lymphoma reveals recurrent h3k27m mutations linked to progression free survival |
| topic | Dog Canine Diffuse large B-cell lymphoma Prognosis Genomics Oncogenetics |
| url | https://doi.org/10.1038/s41598-025-89245-0 |
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