Abstract LB-178: Genomic profiling of 1239 diverse pediatric cancers identifies novel discoveries across tumors
Authors: Chmielecki Juliann , Bailey Mark , He Jie , Elvin Julia , Vergilio Jo-Anne , Ramkissoon Shakti , Suh James , Frampton Garrett M. , Ali Siraj , Ross Jeffrey , Miller Vincent A. , Stephens Philip J. , Lipson Doron 
Published: July 2016

Abstract
Pediatric cancers are rare and diverse entities characterized by low mutational burden. Multiple studies investigating the genomic events driving oncogenesis have identified characteristic diagnostic lesions as well as targets suitable for therapeutic exploitation in common tumor subtypes. Here, we present genomic profiles from 1239 pediatric tumors (ages 0-18) from 51 disease subtypes representing sarcomas (26.6%), other blastomas (22.4%), brain tumors (20.4%), hematological malignancies (19.5%), carcinomas (9.8%), and gonadal tumors (1.4%). This collection represents real-world tumor specimens in which select cancer-associated genes were analyzed for all classes of alterations as part of routine clinical care. Samples were sequenced to a median unique depth of &gt;500x to allow for optimal detection of oncogenic events in low purity specimens. Additionally, 635 samples (51%) were analyzed by targeted RNA-seq for fusions in 265 genes. Alterations with proven clinical actionability in pediatric cancers (BRAF V600E and ALK, NTRK1, and ABL1 fusions) were found in 3.9% of samples from brain, sarcoma, and heme cases. Three novel ALK fusions were identified in a neuroblastoma (BEND5-ALK), a soft tissue sarcoma (IGFBP5-ALK), and an astrocytoma (PPP1CB-ALK). Two novel BRAF fusions were also found in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF). In rhabdomyosarcoma, we identified a novel PAX3-GLI2 fusion and confirmed a second occurrence of the rare PAX3-NCOA1 fusion. This large data set also challenged the paradigm of “disease-specific” alterations as previously characterized fusions involving ALK, NTRK1, and PAX3 were observed in novel diseases from which they were originally reported. We investigated variants of unknown significance for potentially novel cancer mutations, and identified four recurrent and likely somatic variants in KMT2C, PRSS1, and CTNNB1 predicted to have functional impact by in silico analyses. Compared to other large published data sets in neuroblastoma, ALL, AML, rhabdomyosarcoma, and medulloblastoma, similar frequencies of clinically significant alterations were observed, thereby validating this dataset as biologically relevant. While many common and diagnostic alterations have been described in pediatric cancers, researchers are becoming increasingly aware of other rarer, yet equally important, clinically relevant genomic alterations. As demonstrated by the identification of novel fusions and mutations, this data set is ripe with discovery potential, and can be used to generate hypotheses, validate rare findings, and investigate the genomic landscape of rare tumors for which only small studies exist. Data from these 1239 tumors will be publicly available to the research community for exploration and incorporation into future experiments that will ultimately improve the treatment and prognosis for children with cancer.
Citation Format: Juliann Chmielecki, Mark Bailey, Jie He, Julia Elvin, Jo-Anne Vergilio, Shakti Ramkissoon, James Suh, Garrett M. Frampton, Siraj Ali, Jeffrey Ross, Vincent A. Miller, Philip J. Stephens, Doron Lipson. Genomic profiling of 1239 diverse pediatric cancers identifies novel discoveries across tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-178.