title: Isocitrate dehydrogenase-1 is mutated in inflammatory bowel disease-associated intestinal adenocarcinoma with low-grade tubuloglandular histology but not in sporadic intestinal adenocarcinoma.
abstract: The underlying molecular alterations in chronic idiopathic inflammatory bowel disease-associated intestinal adenocarcinoma remain largely unknown. Somatic IDH mutations 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 IDH1 and IDH2 mutations 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 IDH mutations (13% vs. 0%, P=0.047). All IDH mutations were identified in IDH1 and resulted in substitution of arginine by cysteine at position 132 (p.R132C, c.394C>T). IDH1 mutations were frequently (66%) associated with concurrent KRAS mutations (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). IDH1 mutations were also identified in the precursor dysplastic lesions associated with IDH1-positive adenocarcinomas. In conclusion, we demonstrate that IDH1 mutations 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 KRAS mutations. Identification of patients with IDH1-mutated intestinal adenocarcinoma may become clinically important as new therapies emerge that target tumors that harbor IDH mutations.
authors.affiliation: Departments of *Pathology ‡Surgery, University of Pittsburgh Medical Center †Department of Internal Medicine, Division of Gastroenterology §Department of Internal Medicine, Division of Medical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hartman
authors.forename: David
authors.initials: D
authors.lastname: Binion
authors.forename: Miguel
authors.initials: M
authors.lastname: Regueiro
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schraut
authors.forename: Nathan
authors.initials: N
authors.lastname: Bahary
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
authors.forename: Marina
authors.initials: M
authors.lastname: Nikiforova
authors.forename: Reetesh K
authors.initials: RK
authors.lastname: Pai
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics*; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human