Genomic and proteomic profiling of osteosarcoma

Abbreviation

OS

Osteosarcoma

Acknowledgments

This work has been supported in part by funds provided by the Foundation AECC “Proyectos Estratégicos” to F.L.

Introduction

Classical pediatric human osteosarcoma (OS) is considered a heterogeneous entity characterized by inactivation of tumor suppressors, altered oncogene signaling, and/or activation of classical development pathways required for its initiation, maintenance, and dissemination. In recent years, emerging technological advances have allowed better characterization of the genomic (genetic and epigenetic events) and proteomic alterations. Although several robust drivers have been identified, most of these altered entities only contribute marginally to the pathogenesis of OS. This chapter offers a tour d'horizon of the present preclinical and clinical evidence substantiating the relevance of molecular targets that have emerged from genomic and proteomic profiling, and their significance in OS pathogenesis.

Genetic and chromosome alterations

The panoply of genetic alterations associated with sporadic OS development represents the most salient feature of this tumor. OS exhibits complex, unbalanced karyotypes, characterized by numerous recurrent DNA amplifications, deletions, and overt rearrangements with copy number and structural variations, and a high number of somatic mutations. In addition to the inherent chromosomal instability, these events are strongly driven by two mechanisms. Chromotrypsis present in a third of OS is a massive genomic rearrangement acquired in a single catastrophic occurrence responsible for multiple driver events. It is accompanied by kataegis in about half of OS cases, characterized by a cluster of hypermutations occurring near rearrangements break points. The mechanisms influencing these processes include telomere crisis, which occurs by end-to-end fusion, and results in dicentric chromosomes, originating in breakage-fusion–bridge cycles. To overcome telomere attrition, increased telomerase activity and ALT pathway are both common phenomena in OS. ATRX , a gene that encodes for a chromatin-remodeling protein is frequently mutated in OS and accounts for ALT. The mechanisms implicated in kataegis are mostly unknown, but ionizing radiation, which triggers the development of OS, also induces kataegis.

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