Abstract 5102: Correlation analysis of CREBBP mutation with tumor mutation burden and effect of immune checkpoint therapy in bladder cancer

Abstract

Abstract Background: CREB-binding protein (CREBBP, hereafter CBP) encoded the protein having intrinsic histone acetyltransferase activity, which stabilized the additional protein interactions with the transcription complex. The mutation of CREBBP has been reported that caused Rubinstein-Taybi syndrome (RTS) and associated with acute myeloid leukemia, but not been studied in bladder cancer (BLCA). Immune checkpoint therapy (ICI) has significantly became one of the primary treatment of BLCA, and Tumor mutation burden (TMB) has been regarded as the most prevalent biomarker to predict immunotherapy. The CREBBP mutation status correlation with TMB and immune response remain unknown. Methods: Whole exome sequencing (WES) data and clinical data of 406 BLCA patients was obtained from the Cancer Genome Altas (TCGA). The mutation data of 206 FFPE tumor samples from Chinese BLCA patients were sequenced by targeted next-generation sequencing (NGS, 3DMed panel). NGS data and clinical data of 192 advanced BLCA patients treated with ICI were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). The association between CREBBP mutation and TMB level in BLCA were explored. Survival analysis was determined by Kaplan-Meier (KM) analysis. Results: In total, The CREBBP mutation frequency was 16.25% (66/406) of BLCA patients in TCGA, 14.56% (30/206) in Chinese cohort and 13.54 (26/192). In Chinese cohort, the alteration frequency of NOTCH signal pathways affected was 48.54% (100/206), in which the highest frequency genes was CREBBP. The TMB level in CREBBP mutant group was higher than wild-type group both in Chinese group (Wilcoxon test, p = 0.001) and MSKCC cohort (Wilcoxon test, p < 0.001). The survival analysis were performed on patients from TCGA cohorts without treatment information and MSKCC BLCA patients treated with ICIs, separately. In TCGA cohort, there are not significantly difference between CREBBP mutation group (n=65) and wild-type group (n=340). While in MSKCC ICIs treatment cohort, the overall survival (OS) of CREBBP mutation group (n=26) were significantly longer than wild-type group (n=166) (median OS, mutation vs wild-type = NE vs 15 months; HR 0.468 [95% CI 0.26-0.84]; P = 0.0431). Conclusion: The CREBBP gene mutation was associated with higher TMB level. Clinical cohort analysis results suggested that CREBBP might be a predictive biomarker of immune checkpoint therapy but not a prognostic factor in BLCA. Citation Format: Abai Xu, Tingting Chen. Correlation analysis of CREBBP mutation with tumor mutation burden and effect of immune checkpoint therapy in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5102.