Mutations in CREBBP and EP300 HAT and Bromo Domains Drive Hypermutation and Predict Survival in GI Cancers Treated with Immunotherapy

<b>Background:</b> The role of CREBBP and EP300 mutations in hypermutation and immunotherapy response in gastroesophageal adenocarcinomas is poorly defined and needs further investigation. <b>Methods:</b> We conducted an in silico analysis of 12 publicly available studies (n = 1871; cBioPortal), stratifying samples by CREBBP/EP300 status to assess associations with TMB-High, MSI, co-mutation patterns, and mutation localization. Clinical validation was performed in an independent pan-cancer cohort treated with ICIs (n = 1610) and a gastric cancer cohort with WES data (n = 55). <b>Results:</b> Coding mutations in CREBBP and/or EP300 were significantly associated with TMB-high and MSI-high phenotypes (<i>p</i> < 0.001). All studied samples carrying coding mutations in both CREBBP and EP300 exhibited a TMB-high status. PTVs in functional HAT and bromodomain regions were exclusively associated with TMB-high. Incorporating CREBBP and/or EP300 mutation status improved identification of ultra-hypermutated tumors compared with single-gene biomarkers (<i>p</i> < 0.001). Clinically, these mutations predicted improved overall survival in the pan-cancer cohort (median OS 34 vs. 17 months; HR = 0.68, 95% CI 0.52-0.87, <i>p</i> = 0.0026), as well as in bladder (HR = 0.55, <i>p</i> = 0.0337) and gastrointestinal cancer cohorts (HR = 0.31, <i>p</i> = 0.0021) treated with ICIs. In the gastric cancer validation cohort, all tumors with PTVs demonstrated a partial response to anti-PD-1 therapy. <b>Conclusions:</b> We report CREBBP and EP300 coding mutations as novel potential surrogate biomarkers for hypermutation in gastroesophageal adenocarcinomas and demonstrate their association with favorable immunotherapy outcomes, supporting their potential clinical utility for patient stratification.