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Specific Clinical and Biological Features Characterize Inflammatory Bowel Disease–Associated Colorectal Cancers Showing Microsatellite Instability

Magali Svrcek, Jamila El-Bchiri, Alexandra Chalastanis, Emilie Capel, Sylvie Dumont, Olivier Buhard, Carla Oliveira, Raquel Seruca, Céline Bossard, Jean-François Mosnier, Françoise Berger, Emmanuelle Leteurtre, Anne Lavergne-Slove, Marie-Pierre Chenard, Richard Hamelin, Jacques Cosnes, Laurent Beaugerie, Emmanuel Tiret, Alex Duval, Jean-François Fléjou

From the Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Service d'Anatomie Pathologique; Université Pierre et Marie Curie-Paris; Institut National de la Santé et de la Recherche Médicale, U762, Centre d’Etude du Polymorphisme Humain; AP-HP, Hôpital Lariboisière, Service central d'Anatomie et Cytologie Pathologiques; AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie et Nutrition; AP-HP, Hôpital Saint-Antoine, Service de Chirurgie Viscérale, Paris; Service d'Anatomie Pathologique, Hôpital Hôtel-Dieu, Nantes; Service d'Anatomie Pathologique, Centre Hospitalier Lyon Sud, Lyon; Service d'Anatomie Pathologique, Centre Hospitalier Régional et Universitaire de Lille, Pôle Biologie-Pathologie-Parc Eurosanté, Lille; Service d'Anatomie Pathologique Générale, Centre Hospitalier Universitaire de Hautepierre, Strasbourg, France; and Instituto de Patologia e Immunologia Molecular da Universidade do Porto, Porto, Portugal

Address reprint requests to Magali Svrcek, MD, Service d'Anatomie et Cytologie Pathologiques, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, F75571 Paris cedex 12, Paris, France; e-mail: magali.svrcek{at}sat.aphp.fr

Purpose Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency has been reported to occur at variable frequencies in inflammatory bowel disease–associated intestinal neoplasias (IBD-Ns). We investigated a large series of IBD-N for associations between MSI and several biologic and clinical parameters related to tumors, patients, and their treatment.

Patients and Methods A total of 277 IBD-Ns in 205 patients were screened for MSI. Biologic and clinical variables of patients with high levels of DNA microsatellite instability high (MSI-H) were collected and compared with those associated with 33 MSI-H non-IBD colorectal cancers (CRCs).

Results A total of 27 IBD-Ns from 17 patients were found to be MSI-H. Compared with sporadic MSI-H CRCs, patients presented with a younger age at diagnosis, and there was no female predominance and no right-sided predominance. Unlike sporadic MSI-H CRCs, MSI-H IBD-Ns presented with heterogeneous mismatch repair defects involving MLH1, MSH2, MSH6, or PMS2, and a low frequency of MLH1 promoter methylation. They exhibited frequent BRAF mutations and frameshift mutations in genes containing coding repeat sequences.

Conclusion The mechanisms underlying MMR deficiency in MSI-H IBD-Ns are different from those in sporadic MSI-H tumors and seem to be more related to those observed in hereditary MSI-H tumors. However, BRAF mutations were observed in MSI-H IBD-Ns, similar to sporadic MSI-H tumors, but unlike hereditary MSI-H tumors. Finally, the mutational events in target genes for instability are the same in MSI-H IBD-N tumors as in non-IBD sporadic and hereditary colorectal MSI-H cancers, indicating a colon-related repertoire of target gene alterations.

Supported in part by grants from the Association Nationale de Recherche sur le SIDA (Credit No. 03/162) and from the Association pour la Recherche contre le Cancer (Credit No. 3301). J.E.B. and A.C. were recipients of a fellowship from the Ministère Français de la Recherche.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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