{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:07:17Z","timestamp":1740146837562,"version":"3.37.3"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008359","name":"Maag Lever Darm Stichting","doi-asserted-by":"publisher","award":["FP14-04"],"award-info":[{"award-number":["FP14-04"]}],"id":[{"id":"10.13039\/501100008359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Koningin Wilhelmina Onderzoeksprogramma","award":["KWO 2010 - 4720"],"award-info":[{"award-number":["KWO 2010 - 4720"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL\/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Patients were diagnosed with t-GC \u22655 years after treatment for HL\/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3\/6 of MSI t-GCs had <jats:italic>MLH1<\/jats:italic> promoter methylation and 2\/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, <jats:italic>p =<\/jats:italic> 0.04). T-GC was more frequently sGS in HL\/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, <jats:italic>p =<\/jats:italic> 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, <jats:italic>p =<\/jats:italic> 0.02).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL\/TC patients who were treated before 1990, a time period in which HL\/TC treatments were more extensive.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0270591","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T17:34:53Z","timestamp":1658770493000},"page":"e0270591","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular characterization of gastric adenocarcinoma diagnosed in patients previously treated for Hodgkin lymphoma or testicular cancer"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1894-3440","authenticated-orcid":true,"given":"Lisanne S.","family":"Rigter","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petur","family":"Snaebjornsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3859-6941","authenticated-orcid":true,"given":"Efraim H.","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estelle","family":"Altena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9992-0760","authenticated-orcid":true,"given":"Nicole C. 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Clinically Distinct Subtypes, Concordant With Recent Molecular Classifications","volume":"41","author":"S Ahn","year":"2017","journal-title":"Am J Surg Pathol"},{"key":"pone.0270591.ref026","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/modpathol.2016.55","article-title":"A protein and mRNA expression-based classification of gastric cancer","volume":"29","author":"N Setia","year":"2016","journal-title":"Mod Pathol"},{"key":"pone.0270591.ref027","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.humpath.2016.06.003","article-title":"Immunohistochemistry as a surrogate for molecular subtyping of gastric adenocarcinoma","volume":"56","author":"RS Gonzalez","year":"2016","journal-title":"Hum Pathol"},{"key":"pone.0270591.ref028","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nature20805","article-title":"Integrated genomic characterization of oesophageal carcinoma.","volume":"541","author":"Cancer Genome Atlas 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WHO Classification of Tumours of the Digestive System 4th edition 2010."},{"key":"pone.0270591.ref036","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.cancergencyto.2007.09.022","article-title":"Somatic mutations in mismatch repair genes in sporadic gastric carcinomas are not a cause but a consequence of the mutator phenotype","volume":"180","author":"M Pinto","year":"2008","journal-title":"Cancer Genet Cytogenet"},{"key":"pone.0270591.ref037","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1158\/0008-5472.CAN-08-2457","article-title":"E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man","volume":"69","author":"B Humar","year":"2009","journal-title":"Cancer Res"},{"key":"pone.0270591.ref038","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1200\/JCO.2013.50.3409","article-title":"Solid tumors after chemotherapy or surgery for testicular nonseminoma: a population-based study","volume":"31","author":"C Fung","year":"2013","journal-title":"J Clin Oncol"},{"key":"pone.0270591.ref039","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1158\/1055-9965.EPI-09-0250","article-title":"Stomach carcinoma incidence patterns in the United States by histologic type and anatomic site","volume":"18","author":"H Wu","year":"2009","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"pone.0270591.ref040","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/cam4.346","article-title":"Discrimination of p53 immunohistochemistry-positive tumors by its staining pattern in gastric cancer","volume":"4","author":"K Ando","year":"2015","journal-title":"Cancer Med"},{"key":"pone.0270591.ref041","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1200\/JCO.2000.18.3.487","article-title":"Long-term risk of second malignancy in survivors of Hodgkin\u2019s disease treated during adolescence or young adulthood","volume":"18","author":"FE van Leeuwen","year":"2000","journal-title":"J Clin Oncol"},{"key":"pone.0270591.ref042","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1007\/s00535-015-1093-9","article-title":"Recognition of and recent issues in hereditary diffuse gastric cancer","volume":"50","author":"S Sugimoto","year":"2015","journal-title":"J Gastroenterol"},{"key":"pone.0270591.ref043","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.gie.2016.02.028","article-title":"Screening and surveillance for gastric cancer in the United States: Is it needed?","volume":"84","author":"GH Kim","year":"2016","journal-title":"Gastrointest Endosc"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0270591","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T17:35:29Z","timestamp":1658770529000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0270591"}},"subtitle":[],"editor":[{"given":"Tao","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0270591","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2022,7,25]]}}}