Protein expression level of P2RY12 correlates with survival in Non-Small Cell Lung Cancer and exhibits diagnostic potential for Squamous Cell Carcinomas of the Lung

Abstract

P2Y12 receptor (P2RY12), mainly expressed on platelets, is known for its central role in hemostasis. P2RY12 activation is also involved in cancer development through platelet adhesion to cancer cells supporting immune-evasion, promoting tumor angiogenesis and metastasis, among others. P2RY12 is known as an actionable target, and P2RY12 antagonists are in clinical use for cardiovascular diseases. However, very little data are available regarding the protein expression of P2RY12 in lung carcinomas. We performed immunohistochemical staining for P2RY12 in a cohort of non-small cell lung cancer (NSCLC) samples comprising 320 adenocarcinomas (LUAD) and 158 squamous cell carcinomas (LUSC). Results were evaluated using a dual approach combining microscopic assessment and digital image analysis (QuPath). Results were correlated with clinical-pathological data. We found significantly higher P2RY12 protein expression in LUSC compared to LUAD (p<0.001) via eyeballing (absent/low expression in 21.7% (34/158) and moderate/high expression in 78.3% (124/158) of LUSC cases versus absent/low expression in 98.4% (315/320) and moderate/high expression in 1.6% (5/320) of LUAD cases). Digital analysis yielded similar results. High P2RY12 expression was associated with a significantly better 5-year overall survival rate for the entire cohort (p=0.0048) as well as for the LUAD (p=0.015) and LUSC (p=0.05) subgroups. Furthermore, P2RY12 showed excellent discriminatory performance for classifying carcinomas as LUAD or LUSC, with an AUC of 0.916 in ROC-analysis. High P2RY12 expression is linked to a better prognosis and might serve as a promising novel prognostic biomarker for NSCLC. Its assessment could be implemented in future routine diagnostic workup. At the same time, the data suggest that P2RY12 could also serve as a diagnostic marker for LUSC.