Comprehensive pan-cancer analysis of role of GPRASP1, associated with clinical outcomes, immune microenvironment, and immunotherapeutic efficiency in pancreatic cancer

Abstract

Background: GPRASP1 (G-protein-coupled receptor-associated sorting protein 1) plays an important role in tumorigenesis. However, GPRASP1 specific role has not been clearly clarified in cancer, particularly in pancreatic cancer(PC).

Methods: Firstly, we utilized pan-cancer analysis based on RNA sequencing data from TCGA (The Cancer Genome Atlas) to evaluate the expression pattern and immunological role of GPRASP1. Then, through multiple transcriptome datasets (TCGA and Gene Expression Omnibus (GEO)) and multi-omics (RNA-seq, DNA methylation, copy number variations (CNV), somatic mutation data) in-depth analysis, we comprehensively explore the relationship of GPRASP1 expression with clinicopathologic characteristics, clinical outcomes, CNV, and DNA methylation in pancreatic cancer. Additionally, we employed immunohistochemistry (IHC) to further confirm GPRASP1 expression pattern between PC tissues and paracancerous tissues. Lastly, we systematically associated the GPRASP1 with immunological properties from numerous perspectives, such as immune cell infiltration, immune-related pathways, immune checkpoint inhibitors, immunomodulators, immunogenicity, and immunotherapy.

Results: Through pan-cancer analysis, we identified that GPRASP1 plays a critical role in the occurrence and prognosis of PC, and is closely related to immunological characteristics in PC. IHC analysis confirmed that GPRASP1 is significantly down-regulated in PC compared with normal tissues. The expression of GPRASP1 is significantly negatively correlated with clinical features (histologic grade, T stage, and TNM stage), and is an independent predictor of favorable prognosis, regardless of other clinicopathological features (HR: 0.69, 95% CI 0.54-0.92, p= 0.011). The etiological investigation found that the abnormal expression of GPRASP1 was related to DNA methylation and CNV frequency. Subsequently, the high expression of GPRASP1 was significantly correlated with immune cell infiltration (CD8 + T cell, tumor-infiltrating lymphocyte(TIL)), immune-related pathways(cytolytic activity, check-point, human leukocyte antigen (HLA)), immune checkpoint inhibitors (CTLA4, HAVCR2, LAG3, PDCD1 and TIGIT), immunomodulators ( CCR4/5/6, CXCL9, CXCR4/5), and immunogenicity(immune score, neoantigen, TMB(tumor mutation burden)). Finally, IPS (immunophenoscore) and TIDE (tumor immune dysfunction and exclusion) analysis demonstrated that GPRASP1 expression levels can accurately predict the immunotherapeutic response.

Conclusion: GPRASP1 is a promising candidate biomarker that plays a role in the occurrence, development, and prognosis of PC. Evaluating GPRASP1 expression will aid in the characterization of tumor microenvironment (TME) infiltration and orient more efficient immunotherapy strategies.

Keywords: GPRASP1; Immunotherapy; Pan-cancer analysis; Pancreatic cancer; Tumor microenvironment.