Abstract A59: Sequencing identifies diagnostically relevant alterations in pediatric solid tumor patients
Authors: Church Alanna J. , Corson Laura B. , Imamovic-Tuco Alma , Strand Gianna R. , Reidy Dierdre , Doan Duong , Pinches Robert S. , Applebaum Mark A. , Bagatell Rochelle , Crompton Brian D. , DuBois Steven G. , Bender Julia L. Glade , Laetsch Theodore W. , Lee Lobin A. , Lindeman Neal I. , Harris Marian H. , Macy Margaret E. , Maese Luke , Pinto Navin , Sabnis Amit J. , Van Allen Eliezer M. , Vear Susan I. , Weiser Daniel A. , Clinton Catherine M. , Janeway Katherine A. 
Published: August 2020

Abstract
Introduction: Molecular techniques have been incorporated into the diagnostic algorithms for many specific tumors, but the diagnostic role of next-generation sequencing has not been described at a population level. We report diagnostically relevant alterations identified by large-scale sequencing in a prospective cohort of pediatric solid tumors.
Methods and Objectives: Patients are eligible for the GAIN / iCat2 study if they have a high-risk, recurrent, or refractory extracranial solid tumor diagnosed at age 30 or less and have an adequate sample for sequencing available. After informed consent, tumor was sequenced using a next-generation sequencing assay that evaluates 447 genes and includes data about sequence variants, copy number alterations, and, in selected genes, translocations. Some cases received additional sequencing via RNASeq or targeted RNA sequencing for further evaluation of fusions. Diagnostic relevance was determined according to AMP/ASCO/CAP standards and guidelines for the reporting of sequence variants in cancer.
Results: 349 patients were enrolled as of December 31, 2018, and had tumor tissue successfully sequenced. These patients represent 60 unique diagnoses according to the WHO ICD-O classification. The most common single diagnoses were osteosarcoma (n=64), Ewing sarcoma (n=44), and alveolar rhabdomyosarcoma (n=32). For 349 patients, 184 (53%) had one or more genetic alterations that were diagnostically relevant, of which 159 (86%) were structural variants, 16 (8%) were sequence variants, and 9 (5%) were copy number variations. Alterations of high diagnostic relevance include CIC-DUX4 fusions in sarcoma (n=8), TP53 intron 1 rearrangements in osteosarcoma (n=26), DICER1 sequence variants in various tumors (n=7), and BCOR internal tandem duplications in clear-cell sarcoma of kidney and primitive myxoid mesenchymal tumor of infancy (n=3).
Conclusions: Diagnostically relevant alterations were identified in over half of pediatric solid tumor patients evaluated. Gene fusions are particularly prevalent. These results support a role for sequencing that includes robust fusion assessment to inform diagnosis in patients with pediatric solid tumors.
Citation Format: Alanna J. Church, Laura B. Corson, Alma Imamovic-Tuco, Gianna R. Strand, Dierdre Reidy, Duong Doan, Robert S. Pinches, Mark A. Applebaum, Rochelle Bagatell, Brian D. Crompton, Steven G. DuBois, Julia L. Glade Bender, Theodore W. Laetsch, Lobin A. Lee, Neal I. Lindeman, Marian H. Harris, Margaret E. Macy, Luke Maese, Navin Pinto, Amit J. Sabnis, Eliezer M. Van Allen, Susan I. Vear, Daniel A. Weiser, Catherine M. Clinton, Katherine A. Janeway. Sequencing identifies diagnostically relevant alterations in pediatric solid tumor patients [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A59.