Co-Occurring Genomic Alterations in Sarcomas: Secondary Hits That Drive Sarcomagenesis
Beyond the canonical gene fusions that define many sarcoma subtypes, secondary genomic alterations play essential roles in tumor progression through mechanisms including tumor suppressor inactivation, telomere maintenance, and epigenomic dysregulation. This Journal of Pathology review systematically catalogues co-occurring mutations, copy number changes, and transcriptomic signatures across both fusion-driven and complex karyotype sarcomas. The authors argue for incorporating comprehensive NGS profiling into clinical sarcoma workflows to capture clinically actionable secondary alterations.
The original study
The spectrum and significance of secondary (co-occurring) genetic alterations in sarcomas: the hallmarks of sarcomagenesis.
- Authors
- Dermawan JK, Rubin BP
- Journal
- The Journal of pathology
- Type
- Journal Article, Review
- PMID
- 37345731
Original abstract
Bone and soft tissue tumors are generally classified into complex karyotype sarcomas versus those with recurrent genetic alterations, often in the form of gene fusions. In this review, we provide an overview of important co-occurring genomic alterations, organized by biological mechanisms and covering a spectrum of genomic alteration types: mutations (single-nucleotide variations or indels) in oncogenes or tumor suppressor genes, copy number alterations, transcriptomic signatures, genomic complexity indices (e.g. CINSARC), and complex genomic structural variants. We discuss the biological and prognostic roles of these so-called secondary or co-occurring alterations, arguing that recognition and detection of these alterations may be significant for our understanding and management of mesenchymal tumors. On a related note, we also discuss major recurrent alterations in so-called complex karyotype sarcomas. These secondary alterations are essential to sarcomagenesis via a variety of mechanisms, such as inactivation of tumor suppressors, activation of proliferative signal transduction, telomere maintenance, and aberrant regulation of epigenomic/chromatin remodeling players. The use of comprehensive genomic profiling, including targeted next-generation sequencing panels or whole-exome sequencing, may be incorporated into clinical workflows to offer more comprehensive, potentially clinically actionable information. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.