Development and Clinical Validation of a 90-Gene Expression Assay for Identifying Tumor Tissue Origin

The accurate identification of tissue origin in patients with metastatic cancer is critical for effective treatment selection but remains a challenge. The aim of this study is to develop a gene expression assay for tumor molecular classification and integrate it with clinicopathologic evaluations to identify the tissue origin for cancer of uncertain primary (CUP). A 90-gene expression signature, covering 21 tumor types, was identified and validated with an overall accuracy of 89.8% (95% CI, 0.87–0.92) in 609 tumor samples. More specifically, the classification accuracy reached 90.4% (95% CI, 0.87–0.93) for 323 primary tumors and 89.2% (95% CI, 0.85–0.92) for 286 metastatic tumors, with no statistically significant difference (P = 0.71). Furthermore, in a real-life cohort of 141 CUP patients, predictions by the 90-gene expression signature were consistent or compatible with the clinicopathologic features in 71.6% of patients (101/141). Findings suggest that this novel gene expression assay could efficiently predict the primary origin for a broad spectrum of tumor types and support its diagnostic utility of molecular classification in difficult-to-diagnose metastatic cancer. Additional studies are ongoing to further evaluate the clinical utility of this novel gene expression assay in predicting primary site and directing therapy for CUP patients.