TMPRSS2-ERG Fusion Identified by Comprehensive Genomic Profiling Reveals Prostatic Origin in Cancer of Unknown Primary: A Case Report.

Cancer of unknown primary (CUP) comprises a heterogeneous group of malignancies in which the primary site cannot be identified despite comprehensive evaluation. Patients in the unfavorable-risk group have limited therapeutic options and typically receive empirical chemotherapy, which is associated with poor outcomes. Comprehensive genomic profiling (CGP) has emerged as a valuable tool for identifying potential therapeutic targets in advanced or rare solid tumors, including cancer of unknown primary. However, the proportion of actionable alterations remains limited, and genomic findings that do not directly inform treatment selection have received relatively little attention, despite their potential relevance for identifying the tissue of origin. We report the case of a 79-year-old man presenting with multiple lymph node metastases from an unknown primary and clinically localized prostate cancer. Comprehensive genomic profiling was performed on a metastatic lymph node specimen. Although no alterations with immediate therapeutic relevance were identified, a TMPRSS2-ERG fusion was detected, supporting a prostatic origin. This case highlights that comprehensive genomic profiling may contribute not only to therapeutic decision-making but also to the identification of the tissue of origin in diagnostically challenging cases.