Cancer of unknown primary (CUP) is a metastatic disease whereby the primary tumour of origin cannot be identified. Generally, the site of origin is the primary clinical identifier for therapy selection; in its absence CUP cases require unconventional diagnostic methods, such as molecular assays, to direct appropriate targeted therapies and improve patient outcomes. In this study we compared the use of SUPERDx, a targeted gene expression panel for tissue of origin diagnosis, a part of the SUPER cohort study at Peter MacCallum Cancer Centre, with WGS on a 63 year old female patient with prior history of lung cancer who presented with a reoccurrence of unknown origin. We found that panel and WGS were concordant in clinically relevant mutations affecting known cancer genes. However, WGS was superior in identifying a diagnostic mutation signature consistent with exposure to tobacco carcinogens and prior history of lung. WGS resulted in a diagnosis for this patient and guided her targeted therapy. We intend to apply this method of profiling on an initial cohort of 30 CUP patients as per the AGHA flagship. In addition, we will perform WTS to demonstrate the mechanisms of immune dependency or evasion and viral transcription status, and to utilise the tumour derived organoids for personalised drug testing and co-culturing.