{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:46:51Z","timestamp":1787014011794,"version":"build-2736575974"},"reference-count":19,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T00:00:00Z","timestamp":1641513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Polymerase proofreading\u2010associated polyposis (PPAP) and Lynch syndrome, caused by mutated\n                    <jats:italic>POLE<\/jats:italic>\n                    and mismatch repair (MMR) genes, respectively, are associated with adult\u2010onset cancer. PPAP and MMR\u2010deficient tumors are both hypermutated, and each has a unique mutational signature. We describe a 4.5\u2010year\u2010old boy with multiple caf\u00e9 au lait spots who presented with metastatic Sonic Hedgehog\u2010activated medulloblastoma, with partial response to intensive chemotherapy and immunotherapy. The tumor showed microsatellite stability, loss of\n                    <jats:italic>PMS2<\/jats:italic>\n                    nuclear expression, and an exceptionally high tumor mutational burden of 276 Mut\/Mb. Germline molecular analysis revealed an inherited heterozygous pathogenic\n                    <jats:italic>POLE<\/jats:italic>\n                    variant and a de novo heterozygous\n                    <jats:italic>PMS2<\/jats:italic>\n                    pathogenic variant. The tumor featured the MMR, POLE, and POLE+MMR mutational signatures. This is the first description of a di\u2010genic condition, which we named \u201cPOL\u2010LYNCH syndrome,\u201d manifested by an aggressive ultra\u2010mutant pediatric medulloblastoma with a unique genomic signature.\n                  <\/jats:p>","DOI":"10.1111\/cge.14106","type":"journal-article","created":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T02:17:09Z","timestamp":1640830629000},"page":"442-447","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Di\u2010genic inheritance of germline\n                    <i>POLE<\/i>\n                    and\n                    <i>PMS2<\/i>\n                    pathogenic variants causes a unique condition associated with pediatric cancer predisposition"],"prefix":"10.1111","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6097-6457","authenticated-orcid":false,"given":"Orli","family":"Michaeli","sequence":"first","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Schneider Children's Medical Center of Israel  Petach Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagay","family":"Ladany","sequence":"additional","affiliation":[{"name":"Biotechnology and Food Engineering Technion\u2014Israel Institute of Technology  Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayelet","family":"Erez","sequence":"additional","affiliation":[{"name":"Department of Biological Regulation Weizmann Institute of Science  Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shay","family":"Ben Shachar","sequence":"additional","affiliation":[{"name":"Clalit Research Institute and Department of Genetics Schneider Children's Medical Center of Israel  Petach Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shai","family":"Izraeli","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Schneider Children's Medical Center of Israel  Petach Tikva Israel"},{"name":"Sackler Faculty of Medicine Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Lidzbarsky","sequence":"additional","affiliation":[{"name":"Raphael Recanati Genetic Institute Rabin Medical Center\u2013Beilinson Hospital  Petach Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Basel\u2010Salmon","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Raphael Recanati Genetic Institute Rabin Medical Center\u2013Beilinson Hospital  Petach Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Biskup","sequence":"additional","affiliation":[{"name":"CeGaT Center for Genomics and Transcriptomics  Tuebingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosef E.","family":"Maruvka","sequence":"additional","affiliation":[{"name":"Biotechnology and Food Engineering Technion\u2014Israel Institute of Technology  Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1476-7937","authenticated-orcid":false,"given":"Helen","family":"Toledano","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Schneider Children's Medical Center of Israel  Petach Tikva Israel"},{"name":"Sackler Faculty of Medicine Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9855-9472","authenticated-orcid":false,"given":"Yael","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine Tel Aviv University  Tel Aviv Israel"},{"name":"Raphael Recanati Genetic Institute Rabin Medical Center\u2013Beilinson Hospital  Petach Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2503"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102014\u2010102284"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.048"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3202"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.06.013"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12477"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201004002\u20104"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010019\u20100654\u20105"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2017.03.027"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.10011"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/DCR.0000000000001150"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094835"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/J.1460\u20102075.1991.TB07751.X"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.305"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.10.024"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29396"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201020\u20100790"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a004499"}],"container-title":["Clinical 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