Oncogenetic landscape of lymphomagenesis in coeliac disease New Publication
Sascha Cording 1 , Ludovic Lhermitte # 2 3 , Georgia Malamut # 1 4 , Sofia Berrabah # 1 , Amélie Trinquand 1 5 , Nicolas Guegan 1 , Patrick Villarese 2 3 , Sophie Kaltenbach 6 , Bertrand Meresse 7 , Sherine Khater 8 , Michael Dussiot 9 , Marc Bras 10 , Morgane Cheminant 9 11 , Bruno Tesson 12 , Christine Bole-Feysot 13 , Julie Bruneau 14 , Thierry Jo Molina 9 14 , David Sibon 11 , Elizabeth Macintyre 2 3 , Olivier Hermine 9 11 , Christophe Cellier 8 , Vahid Asnafi 2 3 , Nadine Cerf-Bensussan 15 , CELAC network
Source : gut
Pmid : 33579790
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.
Keywords: COELIAC DISEASE; GASTROINTESTINAL LYMPHOMA; GENE MUTATION.