Pediatric Sarcomas: The Next Generation of Molecular Studies

SIMPLE SUMMARY: There has been an incredible amount of discovery in pediatric sarcomas, but much remains to be accomplished. Clinical challenges include diagnostic heterogeneity and the poor outcome of patients with high risk, metastatic, and relapsed disease. The emergence of single cell sequencing has allowed the ability to document tumor cell heterogeneity in amazing detail, but it does not allow the ability to visualize spatial orientation. This problem has been solved by spatial multi-omics, which can be used to map tumors and visualize the distribution of critical transcripts, mutations, and proteins. However, these tools only offer observational data. High-throughput functional genomics provides a powerful way to highlight oncogenic drivers and potential therapy opportunities. Research has been hamstrung by a need for annotated specimens, particularly in post-therapy, relapsed, and metastatic disease, and initial biopsies offer only limited data opportunities. Data complexity, variability, and inconsistency present problems best approached with AI/machine learning. We stand on the threshold of a revolution in cancer cell biology that has the potential for translation into more effective and more directed therapies, particularly for previously recalcitrant diseases. ABSTRACT: Pediatric sarcomas constitute one of the largest groups of childhood cancers, following hematopoietic, neural, and renal lesions. Partly because of their diversity, they continue to offer challenges in diagnosis and treatment. In spite of the diagnostic, nosologic, and therapeutic gains made with genetic technology, newer means for investigation are needed. This article reviews emerging technology being used to study human neoplasia and how these methods might be applicable to pediatric sarcomas. Methods reviewed include single cell RNA sequencing (scRNAseq), spatial multi-omics, high-throughput functional genomics, and clustered regularly interspersed short palindromic sequence-Cas9 (CRISPR-Cas9) technology. In spite of these advances, the field continues to be challenged by a dearth of properly annotated materials, particularly from recurrences and metastases and pre- and post-treatment samples.