Abstract 1322: The DNA methylation signature of the driver gene GPRASP1 serves as an early indicator of progression in prostate cancer

Prostate cancer (PCa) is one of the most common tumors in men in Europe and the United States. Patients with primary localized PCa typically demonstrate long-term survival. However, the disease becomes incurable once it progresses to metastatic PCa. Our research focuses on uncovering the early events in tumorigenesis and progression of PCa using multi-omics strategies. In this study, we identified several methylation driver genes associated with PCa by analyzing RNA sequencing and methylation data from The Cancer Genome Atlas (TCGA) database. The R package Methymix was applied to calculate the methylation driver genes. GPRASP1 was selected for further investigation due to its significant role in predicting PCa prognosis. Our analysis of two GEO datasets revealed that GPRASP1 is downregulated in primary PCa, with even lower expression levels observed in metastatic PCa. This finding was supported by immunohistochemistry results from tissue microarray of PCa patients, demonstrating reduced protein levels. Additionally, we identified the downregulation of GPRASP1 due to DNA methylation in its promoter region, as confirmed by targeted DNA methylation sequencing conducted in PCa and normal cell lines. Simultaneously, the use of DNMT inhibitors was found to reverse this downregulation. To investigate the function of GPRASP1 in PCa, we conducted RNA sequencing following the knockdown of GPRASP1 expression to assess changes in the transcriptome. Additionally, we analyzed its interactome using liquid chromatography-mass spectrometry (LC-MS) following immunoprecipitation. The results suggested that GPRASP1 downregulation may promote tumor metastasis through upregulation of CXCR4 and SERPINE1. Moreover, GPRASP1 appears to play a significant role in tumor immunity. To further elucidate this, we performed tumor infiltration analysis by several algorithms. These analyses revealed that GPRASP1 contributes to suppressing anti-tumor immune responses and promotes the remodeling of the tumor microenvironment, thereby facilitating tumor growth. In conclusion, this research identified methylation driver genes by analyzing data from TCGA patients. We specifically focused on GPRASP1 as a pivotal factor for its roles as a driver and its downstream functions in PCa. This investigation provided insights into the early changes associated with PCa and their connections to tumor initiation and progression. These findings enhance our understanding of the genomic landscape in the early stages of PCa and offer a novel approach for this condition's early diagnosis and treatment. This work was supported by the NSFC Project (82173336, 81972766, 81972420), The Science and Technology Project of Shenzhen (JCYJ20210324104214040), the Medical Research Innovation Project (G030410001). Citation Format: Chengyu Huang, Shuo Fang, Yuhao Cui, Xin Huang, Yuhan Lin, Yichen Xiao, Xinyu Ye, Yi Lu. The DNA methylation signature of the driver gene GPRASP1 serves as an early indicator of progression in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1322.