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

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Pires, Sara Ferreira ; de Barros, Juliana Sobral ; da Costa, Silvia Souza ; do Carmo, Gabriel Bandeira ; Scliar, Marilia de Oliveira ; Lengert, Andre van Helvoort ; Boldrini, Erica ; da Silva, Sandra Regini Morini ; Vidal, Daniel Onofre ; Maschietto, Mariana ; Krepischi, Ana Cristina Victorino

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 24, n. 13, p. 22-pg., 2023-07-01.

Abstract

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). TP53 was the most recurrently mutated gene, with an overall rate of similar to 60%, considering SNVs/indels and CNAs. The most frequent CNAs (similar to 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 RB1 and TP53 germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. PTPRQ, KNL1, ZFHX4, and DMD alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. TNFRSF11B, 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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/10250-7 - Characterization of the epigenetic regulation in human solid paediatric tumours
• Grantee: Mariana Camargo Maschietto
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 18/21047-9 - Childhood cancer: genetic predisposition and mechanisms of origin
• Grantee: Ana Cristina Victorino Krepischi
• Support Opportunities: Regular Research Grants