ABSTRACT The project aims to incorporate emerging technologies in genomics, transcriptomics, epigenomics and proteomics for the analyses of advanced, rare, and pediatric cancers. The project has an additional emphasis on translating the results from these new approaches into clinically actionable information through the development of reportable test results in a CLIA clinical testing lab. The proposal will leverage the capabilities and resources of the Mi-OncoSeq CLIA precision oncology lab, first established in 2013. The Mi-OncoSeq lab has sequenced over ten thousand patient samples to date with integrated analyses of tumor RNA, tumor DNA, and matched normal DNA. This project will incorporate long-read and methylation sequencing, using Nanopore technology as a complement to the existing panel of assays available based on Illumina short-read technology. The laboratory operates a Promethion 24 from Oxford Nanopore in pursuit of these goals. The laboratory is developing improved and accelerated bioinformatic pipelines for use in clinical testing labs. Overall, these new technologies and analytical methods will be applied to our cohorts of advanced, rare and pediatric cancers for improved clinical reporting to aid diagnostic, prognostic, and therapeutic decision- making. Specific areas of research will include the roles of imprinting, structural rearrangement, intergenic mutation, and promoter swapping in the development of these cancers and their mechanisms of therapy resistance.