Analysis of the Mutational Landscape of Osteosarcomas Identifies Genes Related to Metastasis and Prognosis and Disrupted Biological Pathways of Immune Response and Bone Development

• Published in: International journal of molecular sciences Vol. 24; no. 13; p. 10463
• Main Authors: Pires, Sara Ferreira, Barros, Juliana Sobral de, Costa, Silvia Souza da, Carmo, Gabriel Bandeira do, Scliar, Marília de Oliveira, Lengert, André van Helvoort, Boldrini, Érica, Silva, Sandra Regini Morini da, Vidal, Daniel Onofre, Maschietto, Mariana, Krepischi, Ana Cristina Victorino
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.06.2023; MDPI
• Subjects: Algorithms; Analysis; Bone cancer; Bone Development; Bone Neoplasms - genetics; Bone tumors; Cell cycle; Cell growth; chromoanasynthesis; Chromosomes; chromothripsis; Copy number; Development and progression; DNA Copy Number Variations - genetics; Gene mutations; Genes; Genetic aspects; Genomic Instability; Genomics; Heterogeneity; Humans; Immune response; Immune system; Immunity; Medical prognosis; Metastases; Metastasis; Mutation; Operating systems; Osteoprotegerin; Osteosarcoma; Osteosarcoma - genetics; p53 Protein; Prognosis; Proteins; PTPRQ; RB1; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Sarcoma; TP53; Tumor proteins; Tumors; Brazil; RB1; chromoanasynthesis; PTPRQ; chromothripsis; DMD; TNFRSF11B; KNL1; TP53; ZFHX4; osteosarcoma
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241310463

Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian patients, and identified 445 potentially deleterious SNVs/indels and 1176 copy number alterations (CNAs). was the most recurrently mutated gene, with an overall rate of ~60%, considering SNVs/indels and CNAs. The most frequent CNAs (~60%) were gains at 1q21.2q21.3, 6p21.1, and 8q13.3q24.22, and losses at 10q26 and 13q14.3q21.1. Seven cases presented CNA patterns reminiscent of complex events (chromothripsis and chromoanasynthesis). Putative and germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. , , , and alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. , involved in skeletal system development and maintenance, emerged as a candidate for osteosarcomagenesis due to its biological function and a high frequency of copy number gains. A protein-protein network enrichment highlighted biological pathways involved in immunity and bone development. Our findings reinforced the high genomic OS instability and heterogeneity, and led to the identification of novel disrupted genes deserving further evaluation as biomarkers due to their association with poor outcomes.