Human head and neck tumors is a heterogeneous group of mainly epithelial tumors. They show a pronounced variation in terms of genomic alterations, morphology, and clinical outcome. There are few or no therapeutic options available for a substantial number of patients afflicted by these diseases. Our research group has over the last 30 years been instrumental in the characterization of genomic alterations in human head and neck tumors and particularly in the discovery of chromosome translocations and novel oncogenic gene fusions in salivary gland tumors (e.g. Dalin et al. Nat Commun 2017, Andersson et al. J Natl Cancer Inst 2017, Persson et al. PNAS 2009, Kas et al. Nat Genet 1997, Moloney et al. Nat Genet 1996). These tumor type-specific fusions function as oncogenic drivers in their respective tumors and are therefore potential targets for therapy. We are currently performing genomic studies of several human tumor types originating from the head and neck region using for example array comparative genome hybridization, fluorescence in situ hybridization, RT-PCR, and targeted nucleotide sequence analysis. We are also performing functional studies of these alterations using experimental in vitro and in vivo systems such as cell culture and patient-derived xenograft models. Now, we want to expand on our repertoire of methods by including next-generation sequencing. In the proposed project, we will use RNA-seq to discover new fusion oncogenes in human head and neck tumors. In addition, we will use RNA-seq for expression studies and to find point-mutations. We will also analyze potential disease-causing point mutations in these tumors using whole and targeted exome sequencing. These studies will determine the genetic events underlying tumor development and discover new potential targets for therapy in these tumors.