Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia

Abstract

Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.

Keywords: Colon cancer; Crohn disease; Hyperplastic polyp; Serrated dysplasia; Sessile serrated adenoma/lesion; Ulcerative colitis.