{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T04:58:21Z","timestamp":1772600301925,"version":"3.50.1"},"reference-count":23,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21ck0106467"],"award-info":[{"award-number":["JP21ck0106467"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21kk0305014"],"award-info":[{"award-number":["JP21kk0305014"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K10026"],"award-info":[{"award-number":["16K10026"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K22608"],"award-info":[{"award-number":["19K22608"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007786","name":"National Center for Child Health and Development","doi-asserted-by":"publisher","award":["2020B\u20102"],"award-info":[{"award-number":["2020B\u20102"]}],"id":[{"id":"10.13039\/100007786","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM141947"],"award-info":[{"award-number":["R35GM141947"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed whole\u2010exome sequencing in 14 pediatric patients with SMNs, including three brain tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer\u2010predisposing genes (CPGs), which was significantly higher than in the control cohort (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). The identified genes with variants were <jats:italic>TP53<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a02), <jats:italic>DICER1<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a01), <jats:italic>PMS2<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a01), and <jats:italic>PTCH1<\/jats:italic> (<jats:italic>n<\/jats:italic>\u00a0=\u00a01). In terms of the type of subsequent cancer, leukemia and multiple episodes of SMN had an exceptionally high rate of CPG pathogenic variants. None of the patients with germline variants had a family history of SMN development. Mutational signature analysis showed that platinum drugs contributed to the development of SMN in three cases, which suggests the role of platinum agents in SMN development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We highlight that overlapping effects of genetic background and primary cancer treatment contribute to the development of second cancers after treatment of pediatric solid tumors. A comprehensive analysis of germline and tumor samples may be useful to predict the risk of secondary cancers.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.5835","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T12:44:01Z","timestamp":1680785041000},"page":"11264-11273","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Prevalence of pathogenic variants in cancer\u2010predisposing genes in second cancer after childhood solid cancers"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1520-7007","authenticated-orcid":false,"given":"Masanori","family":"Yoshida","sequence":"first","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development  Tokyo Japan"},{"name":"Department of Pediatrics, Graduate School of Medicine Yokohama City University  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiko","family":"Nakabayashi","sequence":"additional","affiliation":[{"name":"Department of Maternal\u2010Fetal Biology Research Institute, National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wentao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital  Tennessee Memphis USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiko","family":"Sato\u2010Otsubo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development  Tokyo Japan"},{"name":"Department of Pediatrics, Graduate School of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin\u2010ichi","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development  Tokyo Japan"},{"name":"Department of Pediatrics, Graduate School of Medicine Yokohama City University  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Ogata\u2010Kawata","sequence":"additional","affiliation":[{"name":"Department of Maternal\u2010Fetal Biology Research Institute, National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoko","family":"Kawai","sequence":"additional","affiliation":[{"name":"Department of Maternal\u2010Fetal Biology Research Institute, National Center for Child Health and Development  Tokyo 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Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryota","family":"Shirai","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development  Tokyo Japan"},{"name":"Department of Pediatrics, Graduate School of Medicine Yokohama City University  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoo","family":"Osumi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development  Tokyo Japan"},{"name":"Children's Cancer Center National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikako","family":"Kiyotani","sequence":"additional","affiliation":[{"name":"Children's Cancer Center National Center for 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