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The association of early (\u226450 years) versus typical onset (&gt;50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS)\u00a0was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Among 971 patients undergoing resection for ICC, 22.7% (<jats:italic>n<\/jats:italic> = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, <jats:italic>p<\/jats:italic> &lt; 0.05) and DSS (36.5% vs. 48.9%, <jats:italic>p<\/jats:italic> = 0.03)\u00a0compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, <jats:italic>p<\/jats:italic> = 0.002) compared with individuals with typical\u00a0onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Early-onset ICC has distinct clinical and genomic\/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1245\/s10434-024-15013-5","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T17:02:26Z","timestamp":1707757346000},"page":"3087-3097","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Early Onset Intrahepatic Cholangiocarcinoma: Clinical Characteristics, Oncological Outcomes, and Genomic\/Transcriptomic Features"],"prefix":"10.1245","volume":"31","author":[{"given":"Diamantis I.","family":"Tsilimigras","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Guglielmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Aldrighetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd W.","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorin","family":"Alexandrescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Poultsides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shishir K.","family":"Maithel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo P.","family":"Marques","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Martel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Pulitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Chaucy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas Groot","family":"Koerkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itaru","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunari","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Aucejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-Feng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7994-9870","authenticated-orcid":false,"given":"Timothy M.","family":"Pawlik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,12]]},"reference":[{"issue":"6","key":"15013_CR1","doi-asserted-by":"publisher","first-page":"443","DOI":"10.3322\/caac.21637","volume":"70","author":"KD Miller","year":"2020","unstructured":"Miller KD, Fidler-Benaoudia M, Keegan TH, Hipp HS, Jemal A, Siegel RL. 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