RT Journal Article SR Electronic T1 Oncogenetic landscape of lymphomagenesis in coeliac disease JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP gutjnl-2020-322935 DO 10.1136/gutjnl-2020-322935 A1 Sascha Cording A1 Ludovic Lhermitte A1 Georgia Malamut A1 Sofia Berrabah A1 Amélie Trinquand A1 Nicolas Guegan A1 Patrick Villarese A1 Sophie Kaltenbach A1 Bertrand Meresse A1 Sherine Khater A1 Michael Dussiot A1 Marc Bras A1 Morgane Cheminant A1 Bruno Tesson A1 Christine Bole-Feysot A1 Julie Bruneau A1 Thierry Jo Molina A1 David Sibon A1 Elizabeth Macintyre A1 Olivier Hermine A1 Christophe Cellier A1 Vahid Asnafi A1 Nadine Cerf-Bensussan A1 , YR 2021 UL http://gut.bmj.com/content/early/2021/02/12/gutjnl-2020-322935.abstract AB 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.