Abstract 2236: A Pan-cancer Analysis of CREBBP as a potential predictor for immune checkpoint therapy
Authors: Li Jiaping , Fan Wenzhe , Zhao Yue , Xue Miao , Chen Tingting , Xie Wenzhuan , Huang Mengli 
Published: July 2021

Background: EP300 (hereafter referred to as p300) and its closely related paralog CREB-binding protein (CREBBP, hereafter CBP) are ubiquitously expressed transcriptional co-activators and major lysine acetyltransferases (KATs) in metazoans. The roles of CREBBP in the pathogenesis of leukemia and malignant lymphomas have been reported before, but not been extensively studied in solid tumors. 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: Next generation sequencing (NGS) and clinical data of 1661 advanced cancer patients treated with ICI were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). NGS (381/733 gene 3DMed panel) was performed on FFPE tumor samples from 17144 Chinese pan-cancer patients (Chinese cohort). The association between CREBBP mutation and TMB level in different tumor types were explored. The statistical significance of CREBBP expression level between normal tissues and tumors in pan-cancer was analyzed by the Wilcoxon test using TIMER2.0.

Results: In total, 7.50% (108/1661) of pan-cancer patients in MSKCC harbored CREBBP mutation and 1.38% (237/17144) in Chinese cohort. In MSKCC cohort, the highest CREBBP mutation frequency tumor type was colorectal cancer (CRC, 14.55%, 16/110), Bladder urothelial carcinoma (BLCA, 14.42%, 31/215) and melanoma (SKCM, 7.5%, 24/320) come in second and third, respectively. While in Chinese cohort, the top three CREBBP mutation frequency tumor types were Small-cell lung cancer (SCLC, 9.86%, 14/142), Bladder Urothelial carcinoma (8.81%, 26/295) and Uterine corpus endometrial carcinoma (UCEC, 5.38%, 12/223), respectively. CREBBP mutation was also associated with higher TMB in both MSKCC cohort (median TMB, mutation vs wild-type = 22.12 vs 5.9 Muts/Mb, P &lt; 0.0001) and Chinese pan-cancer cohort (median TMB, mutation vs wild-type = 43.40 vs 9.00 Muts/Mb, P &lt; 0.0001). The highest median TMB level of CREBBP mutation tumor type was UCEC with 18.63 Muts/Mb (n=65). The CREBBP expression level of some tumor types were significantly up-regulated in tumors compared with normal tissues (p &lt; 0.001), such as Cholangiocarcinoma, Head and Neck cancer and Liver hepatocellular carcinoma. The survival analysis were performed on patients in MSKCC cohort treatment with ICIs. The overall survival (OS) of CREBBP mutation group (n=106) were significantly longer than wild-type group (n=1555) (median OS, not reach vs 17 months; HR 0.54 [95% CI 0·38-0·76]; P &lt; 0.001).

Conclusions: The results indicated that CREBBP gene mutation was associated with a higher TMB level in pan-cancer, and patients harboring these genes mutations might easily benefit from ICIs treatment.

Citation Format: Jiaping Li, Wenzhe Fan, Yue Zhao, Miao Xue, Tingting Chen, Wenzhuan Xie, Mengli Huang. A Pan-cancer Analysis of CREBBP as a potential predictor for immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2236.