Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identifi ed, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specifi c candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplifi cation (identifi ed by whole-genome sequencing) and changes in gene expression as identifi ed by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specifi c SCNAs leads to signifi cant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specifi c dependencies could be identifi ed within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.

This cohort study evaluates the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer.

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations.Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy number alterations. We analyzed 64 prospectively collected plasma samples from 17 pediatric sarcoma patients.Translocations were detected in the pre-treatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy number changes in the pre-treatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and copy number alterations in the plasma of pediatric sarcoma patients. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

Survival of children with cancers has dramatically improved over the past several decades. This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease, and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents. Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities. In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically defined subsets of pediatric leukemias, solid tumors, and brain tumors. .