TY - JOUR T1 - Oncogenetic landscape of lymphomagenesis in coeliac disease JF - Gut JO - Gut DO - 10.1136/gutjnl-2020-322935 SP - gutjnl-2020-322935 AU - Sascha Cording AU - Ludovic Lhermitte AU - Georgia Malamut AU - Sofia Berrabah AU - Amélie Trinquand AU - Nicolas Guegan AU - Patrick Villarese AU - Sophie Kaltenbach AU - Bertrand Meresse AU - Sherine Khater AU - Michael Dussiot AU - Marc Bras AU - Morgane Cheminant AU - Bruno Tesson AU - Christine Bole-Feysot AU - Julie Bruneau AU - Thierry Jo Molina AU - David Sibon AU - Elizabeth Macintyre AU - Olivier Hermine AU - Christophe Cellier AU - Vahid Asnafi AU - Nadine Cerf-Bensussan A2 - , Y1 - 2021/02/12 UR - http://gut.bmj.com/content/early/2021/02/12/gutjnl-2020-322935.abstract N2 - 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. ER -