{"doi":"10.1002/hon.70094_190","title":"190 | ONCOGENESIS OF ENTEROPATHY‐ASSOCIATED T‐CELL LYMPHOMA: EXTENSIVE PARALLEL CLONAL EVOLUTION AND ITS CLINICAL CONSEQUENCES","abstract":"Introduction: Enteropathy-associated T-cell lymphoma (EATL) is the most severe complication of coeliac disease (CD). In 50% of the cases, EATL presents after a varying period of CD, of which a subset after refractory CD (RCD). RCD is a high risk marker for EATL (30%–50% < 5 years) and is suggested as a direct precursor. However, data on the oncogenetic evolution of EATL is limited, and genetic risk factors in proliferations preceding EATL are unclear. This is a requirement for personalized advise and risk management of (R)CD patients. Methods: To cover the evolution of EATL from its presumed precursor stages, we selected samples of patients with RCD with (n = 6) and without (n = 21) progression to EATL within 5 years after diagnosis, and EATL cases (n = 13) with their paired adjacent atypical small cell lymphocytosis (aASCL) in the vicinity of the tumor site. Euroclonality NGS-based T-cell receptor gamma and beta gene rearrangement (TR) analysis and clonotype analysis was performed for 11 EATL/aSCL pairs. For mutation analysis, whole exome sequencing was performed with mean sequence depth of 190x for tumor samples and 285x for RCD and aSCL samples. Somatic mutations were called using Lofreq, and Mutect2. To detect low percentage aberrations, a variant allele frequency cutoff of 1% was chosen for a virtual gene panel of 190 published EATL implicated genes. For copy number aberration (CNA) analysis, shallow whole genome sequencing was performed to approximately 0.2x sequence depth, analyzed by qDNAseq. Results: NGS-based TCR analysis showed shared clonotypes in 9/11 aSCL/EATL pairs in a background of a restricted clonotype pattern in 8/9 aSCLs. In 5 cases, the shared clonotype represented a minor component. Mutation analysis showed sets of shared alterations in aSCL EATL pairs in 6/11 cases next to private alterations in each component, while only sets of private alterations were observed in 5/11 pairs. JAK1/STAT3 mutations were both clonal and subclonal and multiple different (sub)clonal JAK1/STAT3 mutations per sample were common. Similar “redundancy” was seen for various other EATL-implicated genes. Mutations and/or CNAs were observed in in all 6/6 EATL-progressing RCDs and 12/21 non-progressing RCDs. These included JAK/STAT mutations and 1q gains, typical for EATL. Conclusions: EATL oncogenesis does not fit to a stem cell or linear model, but our integrated CNA, mutation and TR clonotype analysis supports EATL oncogenesis with an oligoclonal proliferation of immunophenotypically aberrant, but morphological non-atypical intraepithelial T-cells at the tumor site with extensive genetic evolution and subsequent clonal selection into EATL. JAK/STAT alterations were not identified as uniformly early (clonal) drivers. Common genetic changes were seen in RCD samples, independent of progression to EATL. Therefore, such changes should be refuted as high-risk markers and not serve as a basis for intensified CD/RCD management. Research funding declaration: This work was supported by a grant of the Dutch Digestive Foundation (SK18-27) Keywords: genomics, epigenomics, and other -omics; diagnostic and prognostic biomarkers; extranodal non-Hodgkin lymphoma No potential sources of conflict of interest.","journal":"Hematological Oncology","year":2025,"id":568538,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1473385,"name":"Tjitske Los-de Vries","orcid":null,"position":1,"is_corresponding":false},{"id":1472804,"name":"Jeroen A.C.W. Luijks","orcid":"0000-0001-9974-1551","position":2,"is_corresponding":false},{"id":1472805,"name":"J. Janssen","orcid":"0000-0001-5855-4119","position":3,"is_corresponding":false},{"id":98650,"name":"Jacqueline Egthuijsen","orcid":null,"position":4,"is_corresponding":false},{"id":1472806,"name":"Li Fu","orcid":"0000-0002-0759-8370","position":5,"is_corresponding":false},{"id":253375,"name":"Jeroen Maertzdorf","orcid":null,"position":6,"is_corresponding":false},{"id":12385,"name":"Yongsoo Kim","orcid":"0000-0002-2995-2131","position":7,"is_corresponding":false},{"id":1473386,"name":"Maxine D. Rouvroye","orcid":null,"position":8,"is_corresponding":false},{"id":1472807,"name":"Patricia J.T.A. Groenen","orcid":"0000-0003-4314-228X","position":9,"is_corresponding":false},{"id":1473387,"name":"G. Bouma","orcid":null,"position":10,"is_corresponding":false},{"id":857565,"name":"Daphne de Jong","orcid":"0000-0002-9725-4060","position":11,"is_corresponding":false},{"id":98658,"name":"Bauke Ylstra","orcid":"0000-0001-9479-3010","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:56:52.212268Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}