{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:09:54Z","timestamp":1789610994460,"version":"build-2803163510"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T00:00:00Z","timestamp":1708387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Andalusia Health System","award":["RH-0145-2020"],"award-info":[{"award-number":["RH-0145-2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80\u201390%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis\u2013relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed\/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.<\/jats:p>","DOI":"10.3390\/ijms25052457","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T04:04:14Z","timestamp":1708401854000},"page":"2457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma"],"prefix":"10.3390","volume":"25","author":[{"given":"Antonio","family":"Santisteban-Espejo","sequence":"first","affiliation":[{"name":"Department of Pathology, Puerta del Mar University Hospital, 11009 Cadiz, Spain"},{"name":"Department of Medicine and Surgery, Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain"},{"name":"Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Bernal-Florindo","sequence":"additional","affiliation":[{"name":"Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), 11009 Cadiz, Spain"},{"name":"Department of Pathology, Jerez de la Frontera University Hospital, 11407 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1394-576X","authenticated-orcid":false,"given":"Pedro","family":"Montero-Pavon","sequence":"additional","affiliation":[{"name":"Department of Pathology, Jerez de la Frontera University Hospital, 11407 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Perez-Requena","sequence":"additional","affiliation":[{"name":"Department of Pathology, Puerta del Mar University Hospital, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Atienza-Cuevas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Puerta del Mar University Hospital, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria del Carmen","family":"Fernandez-Valle","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hemotherapy, Puerta del Mar University Hospital, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Villalba-Fernandez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Puerta del Mar University Hospital, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6272-9401","authenticated-orcid":false,"given":"Marcial","family":"Garcia-Rojo","sequence":"additional","affiliation":[{"name":"Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), 11009 Cadiz, Spain"},{"name":"Department of Pathology, Jerez de la Frontera University Hospital, 11407 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10962","DOI":"10.1073\/pnas.91.23.10962","article-title":"Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development","volume":"91","author":"Rajewsky","year":"1994","journal-title":"Proc. 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