Abstract 1774P
Background
The CREB-binding protein (CREBBP) is known to modify histones, as well as non-histone proteins, thereby regulating chromatin accessibility and transcription. Recently, it has been found to acetylate key factors involved in DNA replication, and in different DNA repair processes. Here we explored the relationship between CREBBP mutation and its efficacy of immune checkpoint inhibitors (ICIs).
Methods
215 advanced bladder cancers with next-generation sequencing (NGS) and immunotherapy data obtained from MSKCC cohort were used to explore the association between CREBBP mutation and efficacy of ICIs and tumor mutation burden (TMB). TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. In addition, 413 bladder cancers of TCGA database were used to explore the relationship of CREBBP mutation and TMB. The potential mechanism was explored through RNA data by CIBERSORT in advanced bladder cancers of TCGA database.
Results
In total, 13.95% (30/215) patients in MSKCC cohort harbored CREBBP mutation. In the TCGA cohort, the mutation ratio (12.11%, 50/413) was similar to MSKCC. The TMB level of CREBBP mutation group in MSKCC cohort was significantly higher than wild-type group (Median [IQR]:15.72[12.27-36.40] vs. 7.02 [4.92-14.04], P<0.001). In TCGA cohort, CREBBP mutation patients also had higher TMB (Median [IQR]: 6.00[3.74- 8.66] vs. 4.54[2.52-8.20], P=0.077), although significant difference was not observed. The overall survival (OS) of mutation group was significantly longer than wildtype group (HR [95%CI]: 0.42[0.21-0.88], P=0.017). The Cox proportional-hazards regression demonstrated that CREBBP mutation was significantly associated with better OS (HR [95%CI]: 0.43[0.20-0.92], P=0.030), adjusting for age, gender, metastases or primary, TMB and treatment options. Also, we used CIBERSORT to investigate infiltration of immune cells, but significant difference was not observed.
Conclusions
CREBBP mutation shows a favorable link between CREBBP mutation with efficacy of ICIs. Furthermore, validation of the predictive value of CREBBP in prospective trials and more fundamental exploration are needed in future.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The First Affiliated Hospital of Xiamen University.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.