{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:12:31Z","timestamp":1788232351021,"version":"build-2803163510"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009910","name":"Br\u00f8drene Hartmanns Fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009910","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Torn\u00f8es og H\u00f8yrups Fond"},{"name":"Beckett-Fonden, Aase og Ejnar Danielsens Fond"},{"DOI":"10.13039\/501100004196","name":"Odense University Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Nonfunctioning pituitary neuroendocrine tumors (NFPitNETs) account for \u223c30-35% of PitNETs; \u223c75% arise from the SF1 lineage. Recurrence remains common despite resection (\u223c30% in 10 years), and routine histopathology\/IHC has limited value in predicting recurrence risk. This study evaluated whether DNA methylation profiling improves recurrence risk stratification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Genome-wide tissue methylation (Illumina EPIC v1, 850K) was analyzed in 117 retrospective NFPitNETs with clinical and imaging follow-up. Unsupervised consensus clustering defined methylation-based subgroups, followed by supervised differential methylation analysis to identify cluster-specific differentially methylated probes (DMPs). A classifier was trained using these signatures, with predicted subgroup memberships correlated with regrowth and progression-free survival (PFS). To ensure reliable estimations, longitudinal mixed-effects models were restricted to the interval of model stability (\u223c9 years), reflecting cohort follow-up. External validation was performed in 3 independent cohorts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Five clusters (k1-k5) emerged: 4 SF1-positive-predominant (k1, k2, k3, and k5) and 1 TPIT\/PIT1-enriched NFPitNETs (k4). Among the 562 DMPs, many mapped to genes regulating cell-cycle and immune pathways. Compared with k1-k2, k3, k4, and k5 possessed significantly higher recurrence risk. Within SF1-lineage tumors, k3 exhibited postoperative tumor-volume expansion beginning at \u223c6 years. The methylation-based classifier achieved \u223c97% accuracy in assigning clusters and maintained prognostic separation across independent cohorts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>DNA methylation profiling identifies biologically and clinically distinct NFPitNET subgroups, particularly within the SF1 lineage, and may enhance prediction of recurrence risk. Prospective validation and demonstration of clinical utility are warranted to support integration into precision management workflows.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noaf269","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T12:30:48Z","timestamp":1765197048000},"page":"728-740","source":"Crossref","is-referenced-by-count":2,"title":["DNA methylation profiling predicts postsurgical regrowth in SF1-lineage nonfunctioning pituitary neuroendocrine tumors"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5677-0969","authenticated-orcid":false,"given":"Morten Winkler","family":"M\u00f8ller","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Odense University Hospital (M.W.M., B.H., C.B.P., F.R.P.)"},{"name":"Department of Clinical Research and BRIDGE (Brain Research\u2014Inter Disciplinary Guided Excellence), University of Southern Denmark (M.W.M., B.H., C.B.P., H.B.B., J.K.P., F.R.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grayson A","family":"Herrgott","sequence":"additional","affiliation":[{"name":"Hermelin Brain Tumor Center, Omics Laboratory, Department of Neurosurgery, Henry Ford Health (G.A.H., C.P., A.V.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4603-9504","authenticated-orcid":false,"given":"Marianne Skovsager","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Odense University Hospital (M.S.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Halle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Odense University Hospital (M.W.M., B.H., C.B.P., F.R.P.)"},{"name":"Department of Clinical Research and BRIDGE (Brain Research\u2014Inter Disciplinary Guided Excellence), University of Southern Denmark (M.W.M., B.H., C.B.P., H.B.B., J.K.P., F.R.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian Bonde","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Odense University Hospital (M.W.M., B.H., C.B.P., F.R.P.)"},{"name":"Department of Clinical Research and BRIDGE (Brain Research\u2014Inter Disciplinary Guided Excellence), University of Southern Denmark (M.W.M., B.H., C.B.P., H.B.B., J.K.P., F.R.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning B\u00fcnsow","family":"Boldt","sequence":"additional","affiliation":[{"name":"Department of Clinical Research and BRIDGE (Brain Research\u2014Inter Disciplinary Guided Excellence), University of Southern Denmark (M.W.M., B.H., C.B.P., H.B.B., J.K.P., F.R.P.)"},{"name":"Department of Pathology, Odense University Hospital (H.B.B., J.K.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette K","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Research and BRIDGE (Brain Research\u2014Inter Disciplinary Guided Excellence), University of Southern Denmark (M.W.M., B.H., C.B.P., H.B.B., J.K.P., F.R.P.)"},{"name":"Department of Pathology, Odense University Hospital (H.B.B., J.K.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Powell","sequence":"additional","affiliation":[{"name":"Hermelin Brain Tumor Center, Omics Laboratory, Department of Neurosurgery, Henry Ford Health (G.A.H., C.P., A.V.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Valeria","family":"Castro","sequence":"additional","affiliation":[{"name":"Hermelin Brain Tumor Center, Omics Laboratory, Department of Neurosurgery, Henry Ford Health (G.A.H., C.P., A.V.C.)"},{"name":"College of Human Medicine, Department of Physiology, Michigan State University 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