Molecular profiling of visible polypoid and invisible conventional intestinal-type low-grade dysplasia in patients with idiopathic inflammatory bowel disease

Aims Little is known about the molecular features of visible polyps with low-grade intestinal-type dysplasia in patients with inflammatory bowel disease (IBD). To better understand their origins and biological potential, we sought to genomically profile these lesions and compare them with invisible low-grade dysplasia and sporadic adenomas from non-IBD patients. Methods 22 polyps within areas of colitis, 13 polyps outside areas of colitis, 10 foci of invisible dysplasia from patients with IBD and 6 sporadic tubular adenomas from non-IBD patients were analysed using the OncoPanel assay. Results Polyps arising in areas of colitis showed a greater spectrum of mutations, including APC , KRAS , FBXW7 , TP53 , ARID1A and TCF7L2 . Polyps outside colitis and non-IBD sporadic adenomas showed a limited mutational profile, with APC and CTNNB1 mutations. Invisible dysplasia was characterised by TP53 , CTNNB1 and KRAS alterations. Compared with dysplastic polyps, none of the invisible dysplastic foci showed APC alterations (73%—within colitis; p=0.0001, 92%—outside colitis; p<0.0001, 83%—sporadic adenomas; p=0.001). TP53 mutations were significantly higher in invisible dysplasia (50%) compared with polyps within colitis (9%; p=0.02) and outside colitis (8%; p=0.03). Conclusions Molecular alterations in visible low-grade dysplastic polyps with conventional intestinal-type dysplasia from patients with IBD and sporadic adenomas from non-IBD patients overlap significantly. APC alterations appear to play a major role in the development of visible low-grade dysplastic lesions in patients with IBD, regardless of background colitis. As with IBD-associated colorectal cancers, TP53 mutations are an early event in the development of invisible, low-grade conventional intestinal-type dysplasia in patients with IBD.