Oncogenetic landscape of lymphomagenesis in coeliac disease. Issue 3 (12th February 2021)

• Record Type: Journal Article
• Authors: Cording, Sascha; Lhermitte, Ludovic; Malamut, Georgia; Berrabah, Sofia; Trinquand, Amélie; Guegan, Nicolas; Villarese, Patrick; Kaltenbach, Sophie; Meresse, Bertrand; Khater, Sherine; Dussiot, Michael; Bras, Marc; Cheminant, Morgane; Tesson, Bruno; Bole-Feysot, Christine; Bruneau, Julie; Molina, Thierry Jo; Sibon, David; Macintyre, Elizabeth; Hermine, Olivier; Cellier, Christophe; Asnafi, Vahid; Cerf-Bensussan, Nadine
• Other Names: author non-byline.; Bouhnik Yoram author non-byline.; Cuenod Charles-André author non-byline.; Brechignac Sabine author non-byline.; Allez Matthieu author non-byline.; Cosnes Jacques author non-byline.; Fourmestraux Agnès author non-byline.; Delchier Jean-Charles author non-byline.; Dupuis Jehan author non-byline.; Haioun Corinne author non-byline.; Gnaoui Taoufik El author non-byline.; Lerebours Eric author non-byline.; Savoye Guillaume author non-byline.; Tilly Herve author non-byline.; Flourie Bernard author non-byline.; Coiffier Bertrand author non-byline.; Hebuterne Xavier author non-byline.; Arab Nadia author non-byline.; Filippi Jérôme author non-byline.; Schneider Stéphane author non-byline.; Zerbib Frank author non-byline.; Milpied Noel author non-byline.; Bouabdallah Krimo author non-byline.; Tabrizi Reza author non-byline.; Vigouroux Stéphane author non-byline.; Pigneux Arnaud author non-byline.; Leguay Thibaut author non-byline.; Dilhuydy Marie-Sarah author non-byline.; Dauriac Charles author non-byline.; Bologna Serge author non-byline.; Hulin Cyrille author non-byline.; Bonmati Caroline author non-byline.; Magnin Fréderic author non-byline.; Ranta Dana author non-byline.; Matysiakbudnik Tamara author non-byline.; Deconinck Eric author non-byline.; Pouderoux Philippe author non-byline.; Bonaz Bruno author non-byline.; Gressin Remy author non-byline.; Carbonnel Franck author non-byline.; Gornet Jean-Marc author non-byline.; Branche Julien author non-byline.; Saint-Georges Georgette author non-byline.; Reimund Jean-Marie author non-byline.; Nancey Stéphane author non-byline.; Nachury Maria author non-byline.; Viennot Stéphanie author non-byline.; Zallot Camille author non-byline.; Fabiani Bettina author non-byline.; Marthey Lysiane author non-byline.; Juvin Karine author non-byline.; Baleur Yann Le author non-byline.; Kwiatek Sandy author non-byline.; Saillard Eric author non-byline.; Louvel Dominique author non-byline.; Roblin Xavier author non-byline.; Beau Philippe author non-byline.; Feugier Pierre author non-byline.; Peyrin-Biroulet Laurent author non-byline.; Zanaldi Hélène author non-byline.; Brixi-Benmansour Hedia author non-byline.; Cadiot Guillaume author non-byline.; Lecomte Thierry author non-byline.; Bretagne Jean-Francois author non-byline.; Casasnovas Olivier author non-byline.; Caillot Denis author non-byline.; Bedenne Laurent author non-byline.; Bay Jacques-Olivier author non-byline.; Bouteloup Corinne author non-byline.; Duclos Bernard author non-byline.; Foucaud Carine author non-byline.;
• Is Part Of: Gut. Volume 71:Issue 3(2022)
• Page Start: 497
• Page End: 508
• Publication Date: 2021-02-12
• Subjects: COELIAC DISEASE -- GASTROINTESTINAL LYMPHOMA -- GENE MUTATION; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2020-322935
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. Design: Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines. Results: 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines. Conclusion: Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.