Abstract
From extrachromosomal DNA to neo-peptides, reprogramming of cancer genomes leads to the emergence of cancer state-specific molecules. Here, we systematically identify and characterize a large repertoire of orphan non-coding RNAs (oncRNAs), a class of cancer-emergent small RNAs, across 32 tumor types. We show that oncRNA binary presence-absence patterns represent a digital molecular barcode that captures cancer type and subtype identities. Importantly, this barcode is partially accessible from the cell-free space as cancer cells secrete a subset of oncRNAs. Leveraging large-scale in vivo genetic screens in xenografted mice, we functionally identify driver oncRNAs in multiple tumor types. In a retrospective study across 192 breast cancer patients, we show that oncRNAs are reliably detected in blood and that changes in cell-free oncRNA burden predict both short-term and long-term clinical outcomes. Together, we establish that oncRNAs have potential roles in tumor progression and clinical utility in liquid biopsies for tumor-naive minimum residual disease monitoring.