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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\n                    <jats:italic>TP53<\/jats:italic>\n                    (43%),\n                    <jats:italic>KRAS<\/jats:italic>\n                    (19.90%),\n                    <jats:italic>KMT2D<\/jats:italic>\n                    (12.60%), and\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    (10.30%). Additionally, using pan-cancer analysis, we found similar variants of\n                    <jats:italic>TERT<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-94678-4","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T06:03:49Z","timestamp":1627020229000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genomic alterations and possible druggable mutations in carcinoma of unknown primary (CUP)"],"prefix":"10.1038","volume":"11","author":[{"given":"Hamidreza Aboulkheyr","family":"Es","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamid","family":"Mahdizadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir Abbas Hedayati","family":"Asl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehdi","family":"Totonchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"94678_CR1","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.canep.2019.06.006","volume":"61","author":"E Rassy","year":"2019","unstructured":"Rassy, E. & Pavlidis, N. 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