{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:47:32Z","timestamp":1785923252139,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["25-25-00739"],"award-info":[{"award-number":["25-25-00739"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25-25-00739"],"award-info":[{"award-number":["25-25-00739"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Identifying immunotherapy biomarkers for colorectal cancer (CRC) beyond MSI-high status is challenging. We evaluated CREBBP\/EP300 and POLE\/POLD1 mutations as candidate markers using public cohorts (MSK-CHORD, n = 5493; TCGA, n = 528; MetTropism, n = 24,496; ICI-treated, n = 1610). Regression with SHAP attribution, survival analyses, and pan-cancer transcriptomic profiling (n = 7628) were performed. CREBBP\/EP300 mutations were independently associated with TMB-high MSS tumors (p &lt; 0.00001). The co-mutation group (CREBBP\/EP300 + POLE\/POLD1; CoMut) was the strongest predictor of elevated TMB level (\u03b2 = 3.63; p &lt; 10\u221216; exp(\u03b2) = 37.7) with a median TMB of 155.9 vs. 7.4 and 5.4 Mut\/Mb in single-mutation groups. CoMut also associated with improved survival (HR = 0.57, p = 0.035). In the ICI-treated cohort, both single-mutation groups (CREBBP\/EP300-MUT-only; POLE\/POLD1-MUT-only) and showed longer overall survival than wild type (34 and 28 vs. 17 months; p &lt; 0.05), but only CREBBP\/EP300 mutations independently reduced mortality risk (HR = 0.71, p = 0.0025). All groups shared immune-inflammatory transcriptomic enrichment. These findings support CREBBP\/EP300 mutations as candidate immunotherapy biomarkers, and co-mutations with POLE\/POLD1 define a TMB-high MSS subgroup that could refine TMB testing, pending prospective validation.<\/jats:p>","DOI":"10.3390\/ijms27157027","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:16:22Z","timestamp":1785921382000},"page":"7027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Co-Mutation of CREBBP\/EP300 and POLE\/POLD1 Identifies a TMB-High Subset of MSS CRC"],"prefix":"10.3390","volume":"27","author":[{"given":"Mariia","family":"Gusakova","sequence":"first","affiliation":[{"name":"National Research Center \u201cKurchatov Institute\u201d, 123182 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1189-5597","authenticated-orcid":false,"given":"Fedor","family":"Sharko","sequence":"additional","affiliation":[{"name":"National Research Center \u201cKurchatov Institute\u201d, 123182 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3795-0571","authenticated-orcid":false,"given":"Eugenia","family":"Boulygina","sequence":"additional","affiliation":[{"name":"National Research Center \u201cKurchatov Institute\u201d, 123182 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ksenia","family":"Maksimova","sequence":"additional","affiliation":[{"name":"National Research Center \u201cKurchatov Institute\u201d, 123182 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim","family":"Patrushev","sequence":"additional","affiliation":[{"name":"National Research Center \u201cKurchatov Institute\u201d, 123182 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","unstructured":"The International Agency for Research on Cancer (IARC) (2025, September 26). 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