Abstract
c-Met receptor tyrosine kinase expression is deregulated in many cancers and is associated with tumor progression and metastases. Semi-quantitative IHC methods fail to capture its subcellular expression patterns, which may determine prognosis. We applied a novel tissue image segmentation and quantification method to c-Met on stage I-stage IV colon cancer patients. Simultaneous detection of extracellular c-Met domain, cell membrane and nuclei on TMAs from 583 patients was achieved using CY5 labeled c-Met, CY-2-pan-cadherin, and DAPI. Using curvature and intensity based segmentation, membrane and nuclear regions were segmented, and epithelial and stromal regions were separated. Probability distributions of membrane, nuclei and cytoplasm c-Met were determined, and an automated scoring algorithm assigned c-Met scores to each compartment. An optimal score threshold separating patients into two groups with maximum difference in survival was calculated using a training and test data set. Lower membrane to cytoplasm c-Met score was a significant predictor of shorter survival in stage I (Hazard Ratio (HR)=0.16, p=0.006) and stage II (HR=0.34, p=0.001) patients. We demonstrate for the first time the value of measuring relative expression of c-Met in membrane and cytoplasm for prediction of survival in stage I and II colon cancer patients.
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