Targetable BRAF and RAF1 Alterations in Advanced Pediatric Cancers

作者：Andrew Rankin, Adrienne Johnson, Alison Roos, Geoffrey Sumithran Kannan, Jeffrey A. Knipstein, Nicholas S. Britt, Mark Richard Rosenzweig, James Haberberger, Dean C. Pavlick, Eric Allan Severson, Jo‐Anne Vergilio, Rachel M. Squillace, Rachel Erlich, Pratheesh Sathyan, Stuart Cramer, David E. Kram, Jeffrey S. Ross, Vince A. Miller, Prasanth Reddy, Brian Michael Alexander, Siraj Mahamed Ali, Shakti H Ramkissoon · 发表于：The Oncologist · 年份：2020 · DOI：10.1002/onco.13519 · 被引用次数：31 · 研究领域：Chromatin Remodeling and Cancer、Neuroblastoma Research and Treatments、Protein Degradation and Inhibitors

RAF family protein kinases signal through the MAPK pathway to orchestrate cellular proliferation, survival, and transformation. Identifying BRAF alterations in pediatric cancers is critically important as therapeutic agents targeting BRAF or MEK may be incorporated into the clinical management of these patients. In this study, we performed comprehensive genomic profiling on 3,633 pediatric cancer samples and identified a cohort of 221 (6.1%) cases with known or novel alterations in BRAF or RAF1 detected in extracranial solid tumors, brain tumors, or hematological malignancies. Eighty percent (176/221) of these tumors had a known-activating short variant (98, 55.7%), fusion (72, 40.9%), or insertion/deletion (6, 3.4%). Among BRAF altered cancers, the most common tumor types were brain tumors (74.4%), solid tumors (10.8%), hematological malignancies (9.1%), sarcomas (3.4%), and extracranial embryonal tumors (2.3%). RAF1 fusions containing intact RAF1 kinase domain (encoded by exons 10-17) were identified in seven tumors, including two novel fusions TMF1-RAF1 and SOX6-RAF1. Additionally, we highlight a subset of patients with brain tumor with positive clinical response to BRAF inhibitors, demonstrating the rationale for incorporating precision medicine into pediatric oncology. IMPLICATIONS FOR PRACTICE: Precision medicine has not yet gained a strong foothold in pediatric cancers. This study describes the landscape of BRAF and RAF1 genomic alterations across a diverse spectrum of...