{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:37:11Z","timestamp":1753893431566,"version":"3.41.2"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>Large cell gastrointestinal lymphoma (LCGIL) is the most common extranodal lymphoma in dogs, but its molecular biological backgrounds have not been clarified. In this study, we comprehensively investigated the gene mutations in LCGIL. Whole exome sequencing analysis using four dogs with LCGIL showed mutations in <jats:italic>NACC1<\/jats:italic> gene in two dogs. Further, the six genes known to be mutated in human intestinal T-cell lymphoma, <jats:italic>ASXL3, SOCS3, PRDM1, FYN, TET2,<\/jats:italic> and <jats:italic>ZDBF2,<\/jats:italic> were found to be mutated in one dog. Then, targeted next-generation sequencing analysis was performed to validate these results using additional 31 dogs with LCGIL. As a result, the mutation in <jats:italic>ZDBF2<\/jats:italic> genes were identified in all samples, but the same mutation was ubiquitously observed in all peripheral blood samples. As for the remaining genes, the mutations were not observed in any dogs. The targeted next-generation analysis of whole exon regions of <jats:italic>ZDBF2<\/jats:italic> revealed the other mutations in additional three dogs. In the present study, some mutations in genes related to human intestinal T-cell lymphoma were identified, but common gene mutations were not found among most cases. These results implied the heterogeneity of molecular pathophysiology of canine LCGIL. Further studies are needed to comprehensively analyze genomic and non-genomic molecular aberrations in each canine LCGIL case.<\/jats:p>","DOI":"10.3389\/fvets.2025.1535446","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T06:52:29Z","timestamp":1739947949000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive investigation of gene mutations in canine large cell gastrointestinal lymphoma"],"prefix":"10.3389","volume":"12","author":[{"given":"Naoki","family":"Matsumura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Tsuruta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Goto-Koshino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keijiro","family":"Mizukami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomomi","family":"Aoi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoko","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itsuma","family":"Nagao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taisuke","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ray","family":"Fukuoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aki","family":"Ohmi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James K.","family":"Chambers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuyuki","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukihide","family":"Momozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirotaka","family":"Tomiyasu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1111\/J.1939-1676.1989.TB03082.X","article-title":"Gastrointestinal lymphoma in 20 dogs. A retrospective study","volume":"3","author":"Couto","year":"1989","journal-title":"J Vet Intern Med"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1354\/VP.41-2-141","article-title":"Characterization of lymphocytes in canine gastrointestinal lymphoma","volume":"41","author":"Coyle","year":"2004","journal-title":"Vet Pathol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"440","DOI":"10.2460\/JAVMA.252.4.440","article-title":"Intestinal lymphoma in dogs: 84 cases (1997-2012)","volume":"252","author":"Sogame","year":"2018","journal-title":"J Am Vet Med Assoc"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1177\/0300985817705175","article-title":"Endoscopic cytology for the diagnosis of chronic enteritis and intestinal lymphoma in dogs","volume":"54","author":"Maeda","year":"2017","journal-title":"Vet Pathol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1177\/0300985815591081","article-title":"Changes in Foxp3-positive regulatory T cell number in the intestine of dogs with idiopathic inflammatory bowel disease and intestinal lymphoma","volume":"53","author":"Maeda","year":"2016","journal-title":"Vet Pathol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1101\/GR.194449.115","article-title":"Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background","volume":"25","author":"Elvers","year":"2015","journal-title":"Genome Res"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/S41684-022-00998-X","article-title":"The genomic landscape of canine diffuse large B-cell lymphoma identifies distinct subtypes with clinical and therapeutic implications","volume":"51","author":"Giannuzzi","year":"2022","journal-title":"Lab Anim"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/J.IMMUNI.2016.07.018","article-title":"Interleukin-15-dependent T-cell-like innate intraepithelial lymphocytes develop in the intestine and transform into lymphomas in celiac disease","volume":"45","author":"Ettersperger","year":"2016","journal-title":"Immunity"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1136\/GUTJNL-2020-322935","article-title":"Oncogenetic landscape of lymphomagenesis in coeliac disease","volume":"71","author":"Cording","year":"2022","journal-title":"Gut"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1038\/LEU.2016.13","article-title":"JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma","volume":"30","author":"Nairism\u00e4gi","year":"2016","journal-title":"Leukemia"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1038\/leu.2016.178","article-title":"Mutations in the JAK\/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas","volume":"30","author":"Nicolae","year":"2016","journal-title":"Leukemia"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"4670","DOI":"10.1038\/S41467-021-24836-9","article-title":"Canine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds","volume":"12","author":"Alsaihati","year":"2021","journal-title":"Nat Commun"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1292\/jvms.24-0096","article-title":"Investigation of the mutations in the genes involved in Janus kinase\/signal transducer and activator of transcription pathway in canine large cell gastrointestinal lymphoma","volume":"86","author":"Tsuruta","year":"2024","journal-title":"J Vet Intern Med"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/J.VETIMM.2015.03.005","article-title":"Construction of a multicolor GeneScan analytical system to detect clonal rearrangements of immunoglobulin and T cell receptor genes in canine lymphoid tumors","volume":"165","author":"Goto-Koshino","year":"2015","journal-title":"Vet Immunol Immunopathol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"5027","DOI":"10.1093\/HMG\/DDW335","article-title":"Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population","volume":"25","author":"Momozawa","year":"2016","journal-title":"Hum Mol Genet"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/S13000-021-01173-5","article-title":"Clinicopathological and molecular genomic features of monomorphic epitheliotropic intestinal T-cell lymphoma in the Chinese population: a study of 20 cases","volume":"16","author":"Chen","year":"2021","journal-title":"Diagn Pathol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1084\/JEM.20160894","article-title":"Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2","volume":"214","author":"Moffitt","year":"2017","journal-title":"J Exp Med"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"122314","DOI":"10.1016\/J.LFS.2023.122314","article-title":"An overview of the co-transcription factor NACC1: beyond its pro-tumor effects","volume":"336","author":"Xie","year":"2024","journal-title":"Life Sci"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"a028571","DOI":"10.1101\/CSHPERSPECT.A028571","article-title":"Negative regulation of cytokine signaling in immunity","volume":"10","author":"Yoshimura","year":"2018","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"3716","DOI":"10.3390\/CANCERS14153716","article-title":"Mutations affecting genes in the proximal T-cell receptor signaling pathway in peripheral T-cell lymphoma","volume":"14","author":"Liu","year":"2022","journal-title":"Cancers"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1182\/BLOOD.2019791475","article-title":"Dysregulation of the TET family of epigenetic regulators in lymphoid and myeloid malignancies","volume":"134","author":"Lio","year":"2019","journal-title":"Blood"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.3109\/10428194.2014.953155","article-title":"PRDM1\/BLIMP1: a tumor suppressor gene in B and T cell lymphomas","volume":"56","author":"Boi","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/BJC.2013.281","article-title":"Functional and cancer genomics of ASXL family members","volume":"109","author":"Katoh","year":"2013","journal-title":"Br J Cancer"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/J.YGENO.2008.12.012","article-title":"Identification of the mouse paternally expressed imprinted gene Zdbf2 on chromosome 1 and its imprinted human homolog ZDBF2 on chromosome 2","volume":"93","author":"Kobayashi","year":"2009","journal-title":"Genomics"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1177\/03009858211030523","article-title":"Histopathological features and immunophenotyping of canine transmural gastrointestinal lymphoma using full-thickness biopsy samples","volume":"58","author":"Kojima","year":"2021","journal-title":"Vet Pathol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1111\/VCO.12570","article-title":"Tumour-specific microRNA expression pattern in canine intestinal T-cell-lymphomas","volume":"18","author":"Joos","year":"2020","journal-title":"Vet Comp Oncol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1292\/JVMS.19-0547","article-title":"Genome-wide DNA methylation analysis in canine gastrointestinal lymphoma","volume":"82","author":"Ohta","year":"2020","journal-title":"J Vet Med Sci"}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2025.1535446\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T06:52:31Z","timestamp":1739947951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2025.1535446\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":27,"alternative-id":["10.3389\/fvets.2025.1535446"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2025.1535446","relation":{},"ISSN":["2297-1769"],"issn-type":[{"type":"electronic","value":"2297-1769"}],"subject":[],"published":{"date-parts":[[2025,2,19]]},"article-number":"1535446"}}