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 longstanding 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, 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 to serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include: 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. Additionally, we molecularly profiled specimens from sessile serrated lesion-like (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), 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 SEC or SSL-like/SL-NOS patients. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in IBD patients and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.