Pathogenesis-Guided Biomarker Assessment: A Shift in Prostate Cancer Diagnostics.

Despite prostate cancer being one of the most common malignancies in men, its pathological diagnosis remains plagued by inter-observer variability and diagnostic ambiguity. Traditional morphological assessment and currently available biomarkers such as PSA (Prostate-Specific Antigen), AMACR (Alpha methylacyl CoA racemase), and p63 suffer from poor specificity and clinical reliability. In this review, we present a pathogenesis-guided biomarker discovery strategy that led to the development of a clinically validated biomarker panel-Appl-1, Sortilin, and Syndecan-1. These biomarkers, which reflect fundamental biological processes within the endosome-lysosome system, offer improved diagnostic precision and prognostic utility for patients with prostate cancer. This review discusses the rationale behind their discovery, the multidisciplinary approach that enabled it, the evidence supporting their use, and their implementation in U.S. clinical practice as a lab-developed test (LDT). We propose this approach as a new diagnostic standard that bridges mechanistic insight with real-world application.