The Variable Genomic Landscape During Osteosarcoma Progression: Insights From a Longitudinal WGS Analysis
Genes Chromosomes and Cancer, vol. 63, pp. e23253
Abstract
Osteosarcoma is a primary bone tumor that exhibits a complex genomic landscape characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. We performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence, and distant metastases. A comprehensive analysis of single-nucleotide variants (SNVs), structural variants, copy number alterations (CNAs), and chromothripsis events revealed the genomic heterogeneity during osteosarcoma progression. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during disease progression. Phylogenetic trees based on SNVs and structural variants reveal distinct evolutionary patterns between patients, including linear, neutral, and branched patterns. The majority of osteosarcomas showed variable copy number profiles or gained whole-genome doubling in later occurrences. Large proportions of the genome were affected by loss of heterozygosity (LOH), although these regions remain stable during progression. Additionally, chromothripsis is not confined to a single early event, as multiple other chromothripsis events may appear in later occurrences. Together, we provide a detailed analysis of the complex genome of osteosarcomas and show that five of six osteosarcoma genomes are highly dynamic and variable during progression.
Authors 10
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Debora M. Meijer Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center Leiden Center for Computational Oncology
Leiden University Medical Center
Affiliation as printed
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Leiden Center for Computational Oncology Leiden University Medical Center Leiden The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands
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Dina Ruano Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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Inge H. Briaire‐de Bruijn Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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Pauline M. Wijers‐Koster Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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Michiel A. J. van de Sande Aachen Department of Orthopaedic Surgery Leiden University Medical Center Leiden The Netherlands Department of Orthopaedic Surgery
Leiden University Medical Center
Affiliation as printed
Department of Orthopaedic Surgery Leiden University Medical Center Leiden The Netherlands
Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands
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Hans Gelderblom Aachen Department of Medical Oncology Leiden University Medical Center Leiden the Netherlands Department of Medical Oncology
Leiden University Medical Center
Affiliation as printed
Department of Medical Oncology Leiden University Medical Center Leiden The Netherlands
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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Anne‐Marie Cleton-Jansen Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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Noel F.C.C. de Miranda Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center Leiden Center for Computational Oncology
Leiden University Medical Center
Affiliation as printed
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Leiden Center for Computational Oncology Leiden University Medical Center Leiden The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands
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Marieke L. Kuijjer Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center Leiden Center for Computational Oncology
University of Oslo · Leiden University Medical Center
Affiliation as printed
Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine University of Oslo Oslo Norway
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Leiden Center for Computational Oncology Leiden University Medical Center Leiden The Netherlands
Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine, University of Oslo, Oslo, Norway
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands
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Judith V.M.G. Bovée corresponding Aachen Department of Pathology Leiden University Medical Center Leiden The Netherlands Department of Pathology, Leiden University Medical Center Leiden Center for Computational Oncology
Leiden University Medical Center
Affiliation as printed
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Leiden Center for Computational Oncology Leiden University Medical Center Leiden The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands
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