{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:41:00Z","timestamp":1791931260577,"version":"4.3.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>This study aimed to determine the associations of <jats:italic>MEG3<\/jats:italic> rs7158663, rs4081134 gene variants, as well as the immunohistochemical markers Ki-67, p53, and CK18, with the clinical features of pituitary neuroendocrine tumors (PitNETs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This case-control study included 340 individuals who were divided into two groups: a control group (<jats:italic>n=220<\/jats:italic>) and a PitNETgroup (<jats:italic>n=120<\/jats:italic>). DNA was isolated from the venous blood of study participants by the leukocyte salt precipitation method. Real-time polymerase chain reaction was used for the <jats:italic>MEG3<\/jats:italic> rs7158663, rs4081134 single nucleotide variants genotyping. Immunohistochemical analysis of Ki-67 labeling index and p53 protein biomarkers was performed using the automated Ventana BenchMark ULTRA PLUS staining system, following the manufacturer\u2019s recommendations. CK18 immunostaining was conducted with the Dako Omnis staining system, following the manufacturer\u2019s recommendations. Monoclonal antibodies SP6, DO-7, and DC-10 were used to detect Ki-67 labeling index, p53, and CK18, respectively. Statistical data analysis was performed using the \u201cIBM SPSS Statistics 30.0\u201d program.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genotype and allele frequencies of <jats:italic>MEG3<\/jats:italic> rs7158663 and rs4081134 variants showed no significant differences between healthy controls and PitNET patient groups. Additionally, no associations were found between either <jats:italic>MEG3<\/jats:italic> variants and PitNET recurrence, size, invasiveness, and functional status. Ki-67 labeling index (&amp;gt;3% vs. \u22643%) showed no significant differences with any clinical feature of PitNETs (recurrence, size, invasiveness, functional status). In contrast, the p53 H-score was significantly higher in macroadenomas than in microadenomas (median 27 vs. 16; <jats:italic>p=<\/jats:italic>0.008). Additionally, invasive pituitary adenomas showed a higher p53 H-score compared with non-invasive tumors (median 27 vs. 20; <jats:italic>p=<\/jats:italic>0.018). Negative CK18 immunostaining was significantly more frequent in invasive than non-invasive PitNETs (44.4% vs. 13.3%; <jats:italic>p<\/jats:italic> &amp;lt; 0.001) and in non-functioning compared to functioning adenomas (42.0% vs. 18.4%; <jats:italic>p=<\/jats:italic>0.011). No significant associations were found between either <jats:italic>MEG3<\/jats:italic> variant and Ki-67 LI, p53 H-score, or CK18 immunohistochemical reactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study found that a higher p53 H-score was significantly associated with larger PitNET size and invasiveness. Negative CK18 staining was associated with non-functioning and invasive PitNETs. P53 expression and CK18 status may serve as useful prognostic markers in PitNETs.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1657520","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T04:22:25Z","timestamp":1759983745000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Associations of MEG3 rs7158663, rs4081134 gene variants and Ki-67, p53, CK18 immunohistochemical markers with clinical features of pituitary neuroendocrine tumors"],"prefix":"10.3389","volume":"16","author":[{"given":"Balys Remigijus","family":"Zaliunas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrika","family":"Pileckaite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Duseikaite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurgita","family":"Makstiene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Poskiene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vita","family":"Rovite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Nan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arimantas","family":"Tamasauskas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasa","family":"Liutkeviciene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.5444","article-title":"Diagnosis and management of pituitary adenomas: A review","volume":"329","author":"Tritos","year":"2023","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2214\/AJR.15.14527","article-title":"Visual defects in patients with pituitary adenomas: The myth of bitemporal hemianopsia","volume":"205","author":"Lee","year":"2015","journal-title":"Am J Roentgenology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-3787","article-title":"Excess mortality associated with hypopituitarism in adults: A meta-analysis of observational studies","volume":"100","author":"Pappachan","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnac010","article-title":"Clinical biology of the pituitary adenoma","volume":"43","author":"Melmed","year":"2022","journal-title":"Endocrine Rev"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2007.10.011","article-title":"Nonfunctioning pituitary tumors and pituitary incidentalomas","volume":"31","author":"Molitch","year":"2008","journal-title":"Endocrinol Metab Clinics North America"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO classification of neuroendocrine neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocrine Pathol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s12022-022-09703-7","article-title":"Overview of the 2022 WHO classification of pituitary tumors","volume":"33","author":"Asa","year":"2022","journal-title":"Endocrine Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2016.09.014","article-title":"Predictors of aggressive clinical phenotype among immunohistochemically confirmed atypical adenomas","volume":"34","author":"Zaidi","year":"2016","journal-title":"J Clin Neurosci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1227\/01.NEU.0000349930.66434.82","article-title":"KI-67 in pituitary neoplasms: A review - 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