Isocitrate Dehydrogenase-1Is Mutated in Inflammatory Bowel Disease–associated Intestinal Adenocarcinoma With Low-grade Tubuloglandular Histology but Not in Sporadic Intestinal Adenocarcinoma

The underlying molecular alterations in chronic idiopathic inflammatory bowel disease–associated intestinal adenocarcinoma remain largely unknown. Somatic IDHmutations are often seen in gliomas and myeloid leukemia but have also been recently reported in a subset of other neoplasms. We analyzed a series of intestinal adenocarcinomas with (n=23) and without (n=39) associated chronic idiopathic inflammatory bowel disease treated at our institution for IDH1and IDH2mutations and correlated the clinicopathologic findings with mutation status. Compared with intestinal adenocarcinomas not associated with inflammatory bowel disease, adenocarcinomas associated with inflammatory bowel disease more frequently demonstrated IDHmutations (13 vs. 0, P=0.047). All IDHmutations were identified in IDH1and resulted in substitution of arginine by cysteine at position 132 (p.R132C, c.394C>T). IDH1mutations were frequently (66) associated with concurrent KRASmutations (p.G12D, c.35G>A). IDH1-mutated intestinal adenocarcinomas were seen in the setting of both Crohn disease and ulcerative colitis and were located in both the ileum and colon. Compared with IDH1-negative inflammatory bowel disease–associated adenocarcinoma, IDH1-positive adenocarcinomas more frequently demonstrated tubuloglandular histology (100 vs. 25, P=0.032) and were more frequently associated with precursor lesions exhibiting serrated morphology (66 vs. 6, P=0.034). IDH1mutations were also identified in the precursor dysplastic lesions associated with IDH1-positive adenocarcinomas. In conclusion, we demonstrate that IDH1mutations are occasionally identified in inflammatory bowel disease–associated intestinal adenocarcinoma but not in intestinal adenocarcinoma not associated with inflammatory bowel disease. In addition, IDH1-mutated intestinal adenocarcinoma is associated with a characteristic low-grade tubuloglandular histology and often harbors concurrent KRASmutations. Identification of patients with IDH1-mutated intestinal adenocarcinoma may become clinically important as new therapies emerge that target tumors that harbor IDHmutations.