Abstract 3104: A high prevalence of chromosomal translocations as drivers in high-risk pediatric solid cancers

Abstract

The GAIN iCat2 Project is a collaboration between Dana-Farber/Boston Children9s Cancer and Blood Disorder Center and eleven pediatric oncology centers across the United States to sequence relapsed, metastatic, difficult-to-diagnose, and high-risk extracranial solid tumors from 825 patients. The goals are to gain a better understanding of the genomic events in pediatric cancers and determine the clinical impact of matched targeted therapy. Tumor samples are sequenced on one of four gene panels performed in CLIA certified, CAP accredited laboratories, most often utilizing OncoPanel at the Center for Advanced Molecular Diagnostics, Brigham Women’s Hospital. This panel assesses SNVs and CNVs in 447 cancer-associated genes and interrogates intronic regions of 60 genes frequently involved in oncogenic translocation. For undifferentiated sarcomas and tumors in which oncogenic drivers are not identified by the gene panel, whole exome sequencing or RNA sequencing for fusion detection may be done. Interpretation of genomic results, including potential implications for diagnosis and hereditary risks, as well as assessment of possible matched targeted therapies and suitable trials are summarized in a report to the primary oncology provider. An interim analysis of tumors from the first 275 patients enrolled who have OncoPanel results was performed to assess genomic alterations most prevalent in this group of pediatric cancers. 50% (137/275) have structural alterations in their tumors with over half of these (74/137) harboring an oncogenic fusion that is the main, or only identified, driver of the cancer. These include fusions pathognomonic for diseases such as Ewing sarcoma, alveolar rhabdomyosarcoma, synovial sarcoma, desmoplastic small round cell tumors, mesenchymal chondrosarcoma, low grade fibromyxoid sarcoma, and NUT midline carcinoma. Other cases showed recurrent disruption of key tumor suppressors, such as TP53 intron 1 translocations in osteosarcoma. Lastly, more generalized, key, cancer-driving fusions were seen with rearrangements involving BRAF, NOTCH, and NTRK. In addition to aiding in diagnosis, identification of fusions has led to targeted therapy recommendations for many patients. SNVs and CNVs also helped clarify diagnoses, especially in the case of DICER1 and SMARCB1 alterations, and identified potential targeted therapies to consider for relapsed patients. Although patient recruitment is ongoing, this study shows promise for advancing our understanding and treatment of pediatric cancers and highlights the critical importance of incorporating techniques for fusion detection in tumor profiling. Citation Format: Laura B. Corson, Alma Imamovic-Tuco, Gianna R. Strand, Deirdre Reidy, Duong Doan, Mark A. Applebaum, Rochelle Bagatell, Brian D. Crompton, Steven G. DuBois, Julia L. Glade Bender, AeRang Kim, Theodore W. Laetsch, Lobin A. Lee, Neal I. Lindeman, Laura E. MacConaill, Margaret E. Macy, Luke Maese, Seth Pinches, Navin Pinto, Amit J. Sabnis, Eliezer M. Van Allen, Susan I. Vear, Daniel A. Weiser, Catherine M. Clinton, Katherine A. Janeway, Alanna J. Church. A high prevalence of chromosomal translocations as drivers in high-risk pediatric solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3104.