{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:21:03Z","timestamp":1782706863904,"version":"3.54.5"},"reference-count":37,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["FAPESP\u20102021\/07957\u20105"],"award-info":[{"award-number":["FAPESP\u20102021\/07957\u20105"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Anim Models and Exp Med"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Constitutional mismatch repair deficiency (CMMRD) is a rare disorder resulting from biallelic germline pathogenic variants in mismatch repair genes. This study described the molecular profile of two metachronous brain tumors and a patient\u2010derived xenograft (PDX) from a Brazilian child with CMMRD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>After PDX development, methylation array, whole exome sequencing, and NanoString techniques were applied to describe the genetic landscape of CMMRD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A 6\u00bd\u2010year\u2010old girl was diagnosed with Sonic Hedgehog (SHH)\u2010activated medulloblastoma and somatic\n                      <jats:italic>TP53<\/jats:italic>\n                      \u2010mutant. After surgery and radiochemotherapy, she remained free of disease progression. At 10\u2009years and 3\u2009months, she developed a diffuse pediatric\u2010type high\u2010grade glioma (dpHGG). The child had a family history of cancer, and subsequent investigation revealed a biallelic germline variant on\n                      <jats:italic>MSH6<\/jats:italic>\n                      (c.3556+1G&gt;A) with the absence of protein expression in both normal and tumor tissue. A PDX model of the dpHGG was developed. The methylation profile confirmed the diagnosis of both brain tumors and PDX, refining the classification of dpHGG, Rtk1 subtype, subclass A, with an actionable alteration on Platelet\u2010derived growth factor receptor A\n                      <jats:italic>(PDGFRA)<\/jats:italic>\n                      . Exome analysis showed high tumor mutational burden, with 3019, 540, and 1049 pathogenic variants in the medulloblastoma, dpHGG, and PDX, respectively. Only the medulloblastoma exhibited microsatellite instability. The\n                      <jats:italic>CD24<\/jats:italic>\n                      ,\n                      <jats:italic>CD47<\/jats:italic>\n                      , and\n                      <jats:italic>CD276<\/jats:italic>\n                      immune checkpoints had elevated messenger RNA levels, yet no programmed death ligand 1 expression was observed in CMMRD\u2010derived tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We report an extensive molecular profile of a CMMRD patient, and the developed PDX model can be applied to explore new therapeutic approaches for CMMRD\u2010associated brain tumors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ame2.70069","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:41:01Z","timestamp":1756485661000},"page":"1971-1982","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Establishment and molecular profiling of a\n                    <scp>PDX<\/scp>\n                    model of a metachronous brain tumor in a patient with constitutional mismatch repair deficiency with biallelic\n                    <scp>MSH6<\/scp>\n                    variant"],"prefix":"10.1002","volume":"8","author":[{"given":"Daniel Antunes","family":"Moreno","sequence":"first","affiliation":[{"name":"Molecular Oncology Research Center Barretos Cancer Hospital  Barretos Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna Minniti","family":"Man\u00e7ano","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Barretos Cancer 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