Abstract 3644: Novel NOTCH1-ROS1 gene fusion drives distinct molecular mechanisms in a rare pediatric angiosarcoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13_Supplement), p.3644-3644
• Main Authors: Jain, Payal, Iyer, Sudarshan, Straka, Joshua, Surrey, Lea, Pogoriler, Jennifer, Smith, Tiffany, Busch, Christine, Li, Marilyn, Fox, Elizabeth, Resnick, Adam C., Davare, Monika, Waanders, Angela J.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2019-3644

Angiosarcomas are extremely rare, malignant childhood tumors, which often arise in deep soft tissue and liver as well as exhibit a wide anatomical distribution. Due to the rarity of this diagnosis in pediatrics, the development of novel targeted therapeutic options are limited. Here, we diagnosed a case of pediatric angiosarcoma (pAS), and to identify putative driver genomic aberrations, we performed genomic sequencing via a Comprehensive Next Generation Sequencing Solid Tumor Panel, including RNA-sequencing by anchored multiplex PCR (ArcherDx) for 106 fusion partner genes. We identified a novel NOTCH1-ROS1 gene fusion generated from a rearrangement of chromosomes 9 and 6. Subsequent reverse transcription and Sanger sequencing validated the expression of NOTCH1-ROS1 in the pAs. While both NOTCH1 and ROS1 are established proto-oncogenes, and have been separately involved in gene fusions across diverse cancer types, this is a previously unreported fusion in this rare pediatric cancer. We also identified a germline TP53 p.T123Wfs*12 pathogenic variant on follow-up sequencing, thus revealing Li Fraumeni syndrome in this angiosarcoma patient.Notch1-ROS1 is a novel, uncharacterized fusion protein and its functional oncogenic potential or tumorigenic sufficiency is unknown. We cloned NOTCH1-ROS1 cDNA and generated stably expressing heterologous cell lines to test its oncogenic potential using cellular models of transformation and tumorigenicity. Our analysis revealed that Notch1-ROS1 is a potent oncogene capable of inducing neoplastic transformation in cells, and demonstrated that its expression alone is sufficient for tumor formation in a murine allograft model. Notch1-ROS1 oncogenesis is driven via activation of several downstream pathways through a collaboration between the Notch1 and Ros1 domains. We also tested the efficacy of ROS1-targeted tyrosine kinase inhibitors (TKI) in these model systems; our data show dose-dependent suppression of Notch1-Ros1 driven cellular activity and concurrent inhibition of tumor growth as well as prolonged survival after oral monotherapy.Overall, this study reveals the first known NOTCH1-ROS1 alteration in a case of pAs. Given the extreme rarity of this malignant disease, it is challenging to expand to a larger cohort in a short duration. However, our findings on the mechanistic underpinnings of Notch1-ROS1 provide a deeper understanding of how this novel fusion drives tumor growth. Furthermore, drug-targeting studies provide