A Large‐scale Targeted Proteomics of Plasma Extracellular Vesicles Shows Utility for Prognosis Prediction Subtyping in Colorectal Cancer

Abstract Purpose The pathogenesis of cancers depends on the molecular background of each individual patient. Therefore, verifying as many biomarkers as possible and clarifying their relationships with each disease status would be very valuable. We performed a large‐scale targeted proteomics analysis of plasma extracellular vesicles (EVs) that may affect tumor progression and/or therapeutic resistance. Experimental design Plasma EVs from 59 were collected patients with colorectal cancer (CRC) and 59 healthy controls (HC) in cohort 1, and 150 patients with CRC in cohort 2 for the large‐scale targeted proteomics analysis of 457 proteins as candidate CRC markers. The Mann–Whitney‐Wilcoxon test and random forest model were applied in cohort 1 to select promising markers. Consensus clustering was applied to classify patients with CRC in cohort 2. The Kaplan–Meier method and Cox regression analysis were performed to identify potential molecular factors contributing to the overall survival (OS) of patients. Results In the analysis of cohort 1, 99 proteins were associated with CRC. The analysis of cohort 2 revealed two clusters showing significant differences in OS (p = 0.017). Twelve proteins, including alpha‐1‐acid glycoprotein 1 (ORM1), were suggested to be associated with the identified CRC subtypes, and ORM1 was shown to significantly contribute to OS, suggesting that ORM1 might be one of the factors closely related to the OS. Conclusions The study identified two novel subtypes of CRC, which exhibit differences in OS, as well as important biomarker proteins that are closely related to the identified subtypes. Liquid biopsy assessment with targeted proteomics analysis was proposed to be crucial for predicting the CRC prognosis.