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Effective data sharing is key to accelerating research that will improve the precision of diagnoses, efficacy of treatments and long term survival of pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud based data sharing ecosystem developed via collaboration between St. Jude Children's Research Hospital, DNAnexus, and Microsoft, for accessing, analyzing and visualizing genomic data from >10,000 pediatric cancer patients, long term survivors of pediatric cancer and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabyes on St. Jude Cloud include 12,104 whole genomes, 7,697 whole exomes and 2,202 transcriptomes, which are freely available to researchers worldwide. The resource is expanding rapidly with regular data uploads from St. Jude's prospective clinical genomics programs, providing public access as soon as possible rather than holding data back until publication. Three interconnected apps within the St. Jude Cloud ecosystem Genomics Platform, Pediatric Cancer Knowledgebase (PeCan) and Visualization Community provide a unique experience for simultaneously performing advanced data analysis in the cloud and enhancing the pediatric cancer knowledgebase. We demonstrate the value of the St. Jude Cloud ecosystem through use cases that classify 48 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 subtypes of pediatric cancer. ### Competing Interest Statement C.G.M. has received research funding from Abbvie and Pfizer and served on an advisory board for Illumina. Christopher Meyer, N.T., S.A., T.N., O.S., and T.A. are employees of DNAnexus. B.D., T.A., R.I.D., C.B., G.M., and R.D. are employees of Microsoft.

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