Investigation of CREBBP mutation and correlation with immunotherapy biomarker in Chinese bladder cancer patients.

Abstract

e16537 Background: The CREBBP gene provides instructions for making CREB binding protein, is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. Previous research on CREBBP gene revealed that CREBBP is correlated with tumor occurrence and the efficacy of immune checkpoint inhibitors (ICIs) through directly regulate DNA damage response (DDR) pathway. However, the CREBBP characteristics, its correlation with immunogenic marker, and the predictive value of immunotherapy in bladder cancer was unknown. Methods: An independent cohorts (the MSKCC study cohort) with next generation sequencing (NGS) data from 211 patients with bladder cancer of pan-cancer, which were used to analyze the prognostic effect of CREBBP on immunotherapy. Tumor tissue samples from Chinese bladder cancer were analyzed using NGS (panel on 381/733-gene). TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Estimation of immune filtration cells scores were conducted via TIMER2.0. Results: In MSKCC cohort, there were 30 (14.2%) patients harbored CREBBP mutation ( CREBBPmut), and it (median, 15.71 Muts/Mb) was associated with higher TMB (P ＜0.0001) than the wild-type ( CREBBPwt) (median, 7.81 Muts/Mb). In terms of prognostic effect with ICIs therapy, there was significant difference on overall survival (OS) (HR = 0.43; 95% CI, 0.21–0.90; P = 0.02) between CREBBPmut (median, 12 months) and CREBBPwt (median, 8 months). In Chinese patients, genetic mutation of 184 bladder cancer patients were analyzed with NGS and 24 (13.0%) harbored CREBBPmut, similar to western patients of the MSKCC cohort. In bladder cancer patients with CREBBPmut, the most frequently co-mutated genes were TP53 (71%), followed by ATM (46%), BLM (42%), and BRCA1 (29%). CREBBPmut (median, 15.10 Muts/Mb) was associated with higher TMB (P = 0.0008) than CREBBPwt (median, 9.50 Muts/Mb), which was significant difference. Similarly, there was significant difference in MSI between CREBBPmut and CREBBPwt (P = 0.0095). However, there was no difference in PD-L1 expression between the two groups (P = 0.53). In the immune microenvironment of TCGA-SKCM cohort, only CD4+ T cell (P = 0.022) and activated NK cell (P = 0.042) were significantly higher in CREBBPmut patients. Conclusions: The results showed that the CREBBP gene had a high correlation with TMB and MSI in bladder cancer, and might a potential biomarker for ICIs therapy.