Digital spatial profiling identifies molecular changes involved in development of colitis-associated colorectal cancer

Abstract

Objective: Chronic colonic inflammation seen in inflammatory bowel disease (IBD) is a risk factor for colorectal cancer (CRC). Colitis-associated cancers (CAC) are molecularly different from sporadic CRC. This study aimed to evaluate spatially defined molecular changes associated with neoplastic progression to identify mechanisms of action and potential biomarkers for prognostication. Design: IBD patients who had undergone colectomy for treatment of their IBD or dysplasia were identified from an institutional database. Formalin-fixed paraffin embedded samples from areas of normal, inflamed, dysplastic and adenocarcinoma tissue were identified for digital spatial profiling using the Nanostring GeoMx™ Cancer Transcriptome Atlas. RNA expression and quantification of 1812 genes was measured and analysed in a spatial context to compare differences in gene expression. Results: Sixteen patients were included, nine patients had CAC, two had dysplasia only and five had colitis only. Significant, step-wise differences in gene expression were seen between tissue types, mainly involving progressive over-expression of collagen genes associated with stromal remodelling. Similarly, MYC over-expression was associated with neoplastic progression. Comparison of normal and inflamed tissue from patients who progressed to those who did not also showed significant differences in immune-related genes, including under-expression of thte chemokines CCL18, CCL25 and IL-R7, as well as CD3, CD6 and lysozyme. The known oncogene CD24 was significantly overexpressed. Conclusion: Both tissue types and patient groups are molecularly distinguishable on the basis of their gene expression patterns. Further prospective work is necessary to confirm these differences and establish their clinical significance and potential utility as biomarkers.