The variable genomic landscape during osteosarcoma progression: insights from a longitudinal WGS analysis

medRxiv

Abstract

Abstract Osteosarcoma is a primary bone tumor that exhibits a complex genome 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. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during 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. 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 out of six osteosarcoma genomes are highly dynamic and variable during progression.

Authors 10

1. Debora M. Meijer Aachen 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, 2333 ZA Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

2. Dina Ruano Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

3. Inge H. Briaire‐de Bruijn Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

4. Pauline M. Wijers‐Koster Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

5. Michiel A. J. van de Sande Aachen Department of Orthopaedic Surgery

   Leiden University Medical Center

   Affiliation as printed

   Department of Orthopaedic Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

6. Hans A. J. Gelderblom Aachen Department of Medical Oncology

   Leiden University Medical Center

   Affiliation as printed

   Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

7. Anne‐Marie Cleton-Jansen Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

8. Noel F.C.C. de Miranda Aachen 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, 2333 ZA Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden University Medical Center;

   Leiden University Medical Center

9. Marieke L. Kuijjer Aachen 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, 0318 Oslo, Norway

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   Leiden Center for Computational Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

   University of Oslo

10. Judith V.M.G. Bovée corresponding Aachen 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, 2333 ZA Leiden, The Netherlands

    Leiden Center for Computational Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

    Leiden University Medical Center;

    Leiden University Medical Center