Serum miRNA Assays for detection and management of gastric and lung cancers

Abstract

Background: Lung cancer is the most prevalent cancer and the leading cause of cancer death worldwide. Prognosis remains poor for advanced stage cancer patients. Currently, LDCT is recommended as a screening test for smokers in the U.S. However, the poor specificity (73% specificity at 94% sensitivity) of LDCT has raised significant concern for its high chance of false positive (96% of nodules are benign). Gastric cancer is the 3rd leading cause of cancer deaths worldwide. Currently, endoscopy is the only reliable method for early diagnosis. However, the invasiveness and cost limit its usage as a screening test. MicroRNAs are key regulators of cancer pathogenesis. They are exceptionally stable in body fluids, making them potential noninvasive biomarker for cancers. Method(s): We aim to develop serum miRNA assays to aid screening and early detection of lung and gastric cancers. Lung cancer miRNA biomarkers were identified through a Chinese male smoker case-control cohort (n = 432) and validated in 4 additional cohorts from China, Europe, Singapore and US (n=880). Gastric cancer miRNA bio-markers were identified through a Singaporean case-control cohort (n = 472) and validated in 3 additional cohorts from Singapore, Korea and Japan (n = 467). Multivariate miRNA biomarker panels were formulated by sequence forward floating search and support vector machine using quantitative miRNA expression data. Result(s): More than 600 miRNAs were profiled with MiRXES miRNA qPCR assay platform. Among which, 39 miRNAs were found significantly altered between early-stage lung cancer and matched controls. A six-miR biomarker panel could classify cancer from controls with AUC>0.93 across all cohorts. A 24-miR gastric cancer panel was optimized using discovery set (AUC=0.92) and validated in two blinded studies with fixed algorithm and threshold definition. The 24-miR panel showed 90% sensitivity and 81% specificity in the Korean cohort (AUC=0.91) and had 90% sensitivity and 75% specificity in the Singaporean Chinese cohort (AUC=0.89). Conclusion(s): We have developed serum miRNA panels capable of detecting early-stage lung and gastric cancers. The two miRNA assays are undergoing multi-center prospective clinical validation studies (n> 15, 000) to demonstrate clinical utility.