[en] Enteropathy-associated intestinal T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) have distinctive clinical context, morphology, and immunophenotype. To characterize their genetic and molecular specificities, we compared 30 EATLs and 52 MEITLs by whole-exome, RNA and miRNA sequencing and DNA methylation profiling. Highly recurrent SETD2 loss-of-function alterations and frequent mutations of H3-3A/B consistently altering H3R2, implying deregulation of histone marks, were selectively found in MEITL. EATL instead harbored frequent mutations in TET2, ARID1A, and KMT2D. Highly prevalent JAK-STAT pathway mutations preferentially affected JAK3 and STAT5B in MEITL, and JAK1 and STAT3 in EATL. Half of EATLs contained disruptive mutations in HLA class I genes, impacting class I molecule expression. EATL containing more abundant macrophages was enriched in inflammatory response signatures, with upregulation of CD274, CXCL13, and IDO1 transcripts, suggesting an immunosuppressive tumor microenvironment. CpGs hypomethylated in MEITL compared to EATL were enriched in promoter regions. Unsupervised analyses of mutations, transcription, and methylation profiles concordantly segregated EATLs from MEITLs. In summary, the distinctive genetic, epigenetic, and expression footprints of EATL and MEITL established by this study expand disease-defining features, have diagnostic implications, and provide a rationale for targeted therapies.
Disciplines :
Hematology
Author, co-author :
Vallois, David ; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. David.vallois@chuv.ch
Missiaglia, Edoardo ; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Veloza, Luis; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Fischer, Anja ; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany
Cavalieri, Doriane; Department of Hematology, University Hospital of Lille, Lille, France
Rattina, Vimel ; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Bisig, Bettina ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques ; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Roh, Vincent; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland ; Translational Data Science Facility, AGORA Cancer Research Center, Swiss Institute of Bioinformatics, Lausanne, Switzerland
Wiehle, Laura; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany
Sarkis, Rita; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Bachy, Emmanuel; Department of Hematology, Centre Hospitalier Lyon Sud and Inserm, U1111, Pierre Bénite, France
Bruneau, Julie; Department of Pathology, Necker Hospital for Sick Children, AP-HP, Paris-Cité University, Paris, France
Cairoli, Anne; Service of Hematology, Department of Oncology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland
De Wind, Roland; Department of Pathology, Institute Jules Bordet, Bruxelles, Belgium
Drieux, Fanny; Centre Henri Becquerel, Service of Anatomical and Cytological Pathology, Centre Henri Becquerel, Rouen, France
Dubois, Romain; Department of Pathology, University Hospital of Lille, Lille, France
Emile, Jean-François; Department of Pathology, Ambroise Paré Hospital - Université Saint Quentin en Yvelines, Paris, France
Fataccioli, Virginie; Department of Pathology, AP-HP, Henri Mondor Hospital, F-94010, Créteil, France ; University Paris Est Créteil, INSERM, IMRB, Créteil, France
Laribi, Kamel; Department of Hematology, Hospital Centre Le Mans, Le Mans, France
Ledoux-Pilon, Albane ; Department of Pathology, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France
Lemonnier, François ; University Paris Est Créteil, INSERM, IMRB, Créteil, France ; AP-HP, Henri Mondor Hospital, Lymphoid malignancies unit, Créteil, France
Llamas-Gutierrez, Francisco; Department of Pathology, University Centre Hospital, Rennes, France
Morel, Pierre ; Department of Hematology, Hospital of Lens, Lens, France and Department of Hematology, University Hospital of Amiens, Amiens, France
Parrens, Marie; Department of Pathology, Bordeaux University Hospital, Bordeaux University, Bordeaux, France
Poullot, Elsa; Department of Pathology, AP-HP, Henri Mondor Hospital, F-94010, Créteil, France ; University Paris Est Créteil, INSERM, IMRB, Créteil, France
Quintanilla-Martinez, Leticia; Institute of Pathology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany
Sandrini, Jeremy; Department of Pathology, Le Mans Hospital Center, Le Mans, France
Somja, Joan ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Xerri, Luc; Institut Paoli-Calmettes, CRCM and Aix-Marseille University, Marseille, France
Tournilhac, Olivier ; Department of Hematology, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France
Gaulard, Philippe; Department of Pathology, AP-HP, Henri Mondor Hospital, F-94010, Créteil, France ; University Paris Est Créteil, INSERM, IMRB, Créteil, France
Siebert, Reiner ; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany ; German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm, Germany
de Leval, Laurence ; Université de Liège - ULiège > Département des sciences cliniques ; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. Laurence.deleval@chuv.ch
SNF - Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung SKL - Schweizerische Krebsliga
Funding text :
Supported by the Swiss National Science Foundation (grant 310030_172954), the Swiss Cancer League (grant KLS-4293-08-2017), TRANSCAN-2 (TRS-2018-00000775). The authors acknowledge the support provided by the histopathology, immunopathology and molecular pathology facilities, and the digital pathology platform of the Institute of Pathology of Lausanne. They also thank Dr. Amedeo Sciarra and Dr. Sc. Adamantia Kapopoulou for their contribution to data coding and collection. They also thank Dr. Sc. Baptiste Guey for his support with data analysis.
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