Insights from the genetic and transcriptional characterization of a cancer of unknown primary (CUP).

Cancer of unknown primary (CUP) defines a heterogeneous group of metastatic tumors that lack an identifiable primary tumor, despite a standardized diagnostic work-up (Fizazi et al, 2015). CUPs are characterized by an aggressive clinical course, unusual metastatic pattern, and poor prognosis. Research in this field has been encouraged to unravel the complexity of this enigmatic entity and improve clinical management and survival of CUP patients. In this issue of EMBO Molecular Medicine, Benvenuti et al (2020) describe the molecular characterization of multiple synchronous and spatially distinct metastases from a CUP patient, shedding light on the evolutionary dynamic and distinctive features of CUP.