Introduction:
Carcinoma of Unknown Primary (CUP) is a heterogeneous and metastatic disease where the primary
site of origin is undetectable. Currently, chemotherapy is the only state-of-art treatment option
for CUP patients. The molecular profiling of the tumour, particularly mutation detection, offers a
new treatment approach for CUP in a personalized fashion using targeted agents. We analyzed the
mutation and copy number alterations profile of 1709 CUP samples deposited in the AACR Project
Genomics Evidence Neoplasia Information Exchange (GENIE) cohort and explored potentially
druggable mutations. We identified 52 significant mutated genes (SMGs) among CUP samples, in
which 13 (25%) of SMGs were potentially targetable with either drugs are approved for the know
primary tumour or undergoing clinical trials. The most variants detected were TP53 (43%), KRAS
(19.90%), KMT2D (12.60%), and CDKN2A (10.30%). Additionally, using pan-cancer analysis, we found
similar variants of TERT promoter in CUP and NSCLC samples, suggesting that these mutations may
serve as a diagnostic marker for identifying the primary tumour in CUP. Taken together, the mutation
profiling analysis of the CUP tumours may open a new way of identifying druggable targets and
consequently administrating appropriate treatment in a personalized manner.
