Charles G. Mullighan, Kim E. Nichols, James R. Downing, Lu Wang, Alberto S. Pappo, Amar J. Gajjar, Kirby Birch, Alexander M. Gout, Jinghui Zhang, Michael Macias, Scott G. Foy, Scott Newman, Elizabeth M Azzato, David W. Ellison, Chimene Kesserwan, Michael Rusch, Clay McLeod, Sheila A. Shurtleff, Joy Nakitandwe, and Antonina Silkov
10019 Background: As tumor and germline genomic data from pediatric cancer patients is scarce in existing genomic databases, there is an urgent need for more comprehensive datasets. Such data will allow us to fully assess the actionable pediatric cancer genome, facilitate biomarker discovery, and identify new clinical associations. Methods: We sequenced 1002 tumor/normal pairs as part of a real-time clinical genomics service including whole genome, exome and transcriptome for 775 and exome/transcriptome for 227 samples. Tumor types were representative of the common and rare diseases treated at our institution (37% hematological, 31% brain and 32% solid tumors). A multidisciplinary team assessed every case, and after clinical reporting was complete, genomics data and basic clinical information (primary diagnosis, age, sex, ethnicity, primary/relapse/metastasis status), was made securely available online through St. Jude Cloud (www.stjude.cloud). Results: Based on analysis of 253 initial cases from the Genomes for Kids study, our multi-platform sequencing approach uncovered diagnostic, prognostic and/or therapeutically relevant findings in 78% of patients. We estimate 11-16% of clinically-relevant gene mutations could be missed by less comprehensive sequencing approaches. One quarter of patients had a potentially druggable mutation. This surprisingly high proportion was driven, in part, by BRAF fused low-grade gliomas and diverse JAK/STAT pathway alterations in B-Cell acute lymphoblastic leukemias. Whole genome/transcriptome sequencing allowed us to detect rare and novel gene fusions in 8% of cases and facilitated discovery of a new recurrent fusion gene in pediatric melanoma. All data is available online for others to mine and it is likely that additional clinically-relevant mutations can be uncovered. Conclusions: These data demonstrate the value of incorporating comprehensive sequencing into clinical diagnostics and patient care. We endeavor to make this large and richly annotated dataset available to others in real time rather than holding it back for months or years until publication. We anticipate adding approximately 500 additional cases per year at regular intervals, and as the resource grows, expect users to identify new targetable alterations that may be incorporated into patient care.