A, Among 55 cases of cancer of unknown primary (CUP) origin sequenced, 28 (50.9%) were reclassified to a definitive diagnosis through RNA sequencing tissue of origin predictor. An additional 4 cases in the MET1000 cohort with presumed known diagnoses at study entry were also reclassified. B, Sequencing results were highly informative for patients with CUP, with a total of 34 of 55 CUP cases (61.8%) having at least 1 of the following: (1) a change in cancer diagnosis (28 patients [50.9%]), (2) receipt of sequencing-directed therapy (SDT) (13 patients [23.6%]), or (3) identification of a pathogenic germline variant (PGV) conferring increased cancer risk (8 patients [14.5%]). NET indicates neuroendocrine tumor; NSCLC, non–small cell lung cancer; and SCC, squamous cell carcinoma.