MDB-32. TRANSLATION OF NON-CANONICAL OPEN READING FRAMES AS A CANCER CELL SURVIVAL MECHANISM IN CHILDHOOD MEDULLOBLASTOMA

Abstract High-risk medulloblastoma is one of the most recalcitrant pediatric cancers, and children with MYC-amplified disease frequently succumb to relapsed disease. Extensive analyses coding genome in this have characterized additional somatic events some subsets patients, though tumors lack targetable mutations do not yield insights regarding their aggressive behavior. At same time, known exhibit extensive rewiring translational control MYC-driven tumors, consistent recent genetic evidence that impact transcription factor on mRNA translation may be critical aspect its function during tumorigenesis. Therefore, propose previously unknown mechanisms for disease, we investigated functional non-canonical open reading frames (ORFs) across model systems. We demonstrate these ORFs are commonly translated systems patient correlating subtype. Using genome-wide CRISPR/Cas9 screens, found essential cell survival describe widespread reliance upstream (uORFs) particular. From these, identify a uORF ASNSD1 gene selectively upregulated required maintenance by coordinating prefoldin-like complex, poorly understood complex implicated post-translational control. Together, our findings provide blueprint oncogenic uORFs as mediators both and, extension, human cancers more broadly.