The signature was then applied to the transcriptome obtained from paraffin-embedded tissues of a retrospective cohort of patients, encompassing (i) 15 CUPs, including those matched with four agnospheres (Supplementary Tables 1 and 2); (ii) three metastatic BRAF-mutated melanomas (including mMEL321 that originated mMS321), chosen as positive controls for trametinib sensitivity; and (iii) ten metastases from early metastatic, non-CUP patients (i.e., enrolled as potential CUPs, but whose tissue of origin was then identified (Supplementary Table 1). This evidence concerns the gene BRAF and melanoma.