Objective Liquid biopsies are being rapidly used in adult cancers as new biomarkers of disease. Circulating tumor DNA (ctDNA) levels have been reported to be proportional to disease burden, correlate with treatment response, and predict relapse. However, little is known about how frequently ctDNA is detectable in pediatric patients with solid tumors. Therefore, we developed a next-generation sequencing approach to detect and quantify ctDNA in the blood of patients with the most common pediatric solid tumors. Methods Detection of ctDNA requires assays sensitive to somatic events typically observed in the cancer type being studied. In pediatric solid tumors, structural variants are more common than recurrent point mutations. We adapted an ultralow passage whole-genome sequencing approach to capture copy number variants and a hybrid capture sequencing assay to detect translocations in liquid biopsy samples from pediatric patients. Results Copy number changes seen by ultralow passage whole-genome sequencing enabled detection of ctDNA in patients with osteosarcoma, neuroblastoma, alveolar rhabdomyosarcoma, and Wilms tumor. In Ewing sarcoma, detection of the EWSR1 translocation was a more sensitive approach. For patients with samples collected at multiple time points, changes in ctDNA levels corresponded to treatment response. We also found that disease-specific genomic biomarkers of prognosis were detectable in ctDNA. Conclusion This study demonstrates that liquid biopsy approaches that detect somatic structural variants are well suited to pediatric solid tumors. We show that children with the most common solid tumor malignancies have detectable levels of ctDNA, which may be used to track disease response and identify genomic subclassifiers of disease. Efforts to profile larger collections of clinically annotated specimens are under way to validate the clinical use of these assays.
Background Genomic tumor profiling (GTP) plays an important role in the care of many adult cancer patients. Its role in pediatric oncology is still evolving, with only a subset of patients currently expected to receive clinically significant results. Little is known about perspectives of pediatric oncology patients/parents on GTP. Procedure We surveyed individuals who previously underwent GTP through the iCat (Individualized Cancer Therapy) pilot study of molecular profiling in children with relapsed, refractory, and high-risk solid tumors at four pediatric cancer centers. Following return of profiling results, a cross-sectional survey was offered to the patient, if ≥18y at enrollment, or parent, if <18y. Forty-five surveys (85% response) were completed. Results Eighty-nine percent (39/44) of respondents reported hoping participation would help find cures for future patients, while 59% (26/44) hoped it would increase their/their child’s chance of cure. Most had few concerns about GTP, but 12% (5/43) worried they would learn their/their child’s cancer was less treatable or more aggressive than previously thought. Sixty-four percent (29/45) reported feeling their participation had helped others, and 44% (20/45) felt they had helped themselves/their own child, despite only one sub-study subject receiving targeted therapy matched to GTP findings. Fifty-four percent (21/39) wished to receive all available profiling data, including findings unrelated to cancer and of unclear significance. Conclusions Participants in pediatric GTP research perceive benefits of GTP to themselves and others, but expectations of personal benefits of GTP may exceed actual positive impact. These issues warrant consideration during consent discussions about GTP research participation.
Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.
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