Identification of basement membrane-related signatures for estimating prognosis, immune infiltration landscape and drug candidates in pancreatic adenocarcinoma.

Abstract

Background: Pancreatic adenocarcinoma (PAAD) is a frequent digestive system cancer, which has high mortality and bad outcome. However, the role of basement membrane (BM)-related gene in assessing patient's outcome, microenvironment and treatment response remain unclear. Methods: Basement membrane (BM)-associated genes were detected by univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses using data from the TCGA databases. A risk score system was constructed to distinguish patients in the high- and low-risk groups. Prognostic gene distribution in various immune cell forms was explored through scRNA-seq. Immune cell infiltration was assessed using CIBERSORT and ESTIMATE. The IC50 of common chemotherapeutic drugs and useful molecule compounds were evaluated. The mRNA and protein expression of important signatures were validated utilizing GEPIA and HPA databases. Results: Compared to low risk PAAD patients, PAAD patients with high risk showed a significant much worse overall survival (OS). Risk score of BM-associated genes could estimate patient outcome well, and areas under the curve (AUC) of receiver operating characteristic (ROC) survival curve were 0.76, 0.85, and 0.85 at 1-, 3-, and 5-year. Clinical impact curve (CIC) curve demonstrated the clinical importance of risk score. scRNA-seq revealed that BM-related genes were mainly distributed in malignant cells. Significant variations existed in the immune microenvironment, immune checkpoint expression and chemotherapy response between the studied groups. Furthermore, the mRNA expression levels of FAM83A, LY6D, MET, MUC16, MYEOV, and WNT7A were elevated in PAAD tissues, while the protein expression patterns of LY6D, MET, MUC16, and WNT7A were higher in tumor sample. RO-90-7501, Scriptaid, TG-101348, XMD-892, and XMD-1150 may be valuable small molecule drugs to treat PAAD. Conclusions: In conclusion, we develop a novel BM-related gene signature provide new insights and targets for the diagnosis, outcome estimation, candidate drugs and therapy management of PAAD patients.