Alpha thalassemia/mental retardation X-linked (ATRX) protein expression in human pituitary neuroendocrine tumours and its reported correlation to prognosis and clinical outcomes: A systematic review

Abstract Mutations in Alpha thalassemia/mental retardation X-linked (ATRX) have been implicated in several cancers, including gliomas, sarcomas, neuroendocrine tumors, and other mesenchymal malignancies. ATRX loss contributes to oncogenesis, accelerates tumor growth, and reduces survival by disrupting epigenetic and telomere mechanisms. Additionally, ATRX loss can increase tumor sensitivity to treatment therapies. While research has explored ATRX expression in many cancers, data on its relationship to prognosis in pituitary neuroendocrine tumors (PitNETs) remain inconsistent. This systematic review aims to summarize all available studies on ATRX mutations and expression in PitNETs. A systematic search of PubMed, Scopus, and EMBASE databases was conducted to identify publications between 2014 and 2025 that investigated ATRX mutations or expression in PitNETs, following PRISMA 2020 guidelines. Of 32 identified studies, ten met the inclusion criteria, covering a total of 513 PitNETs. Only 20 tumors (3.9%) showed a loss of ATRX expression. Among these, 60% exhibited corticotropic pathology, while 20% displayed lactotrophic pathology. A small subset of tumors (30%) was classified as pituitary carcinomas with aggressive and proliferative characteristics. Additionally, 10% demonstrated the alternative lengthening of telomeres (ALT) phenotype, 50% had concurrent TP53 mutations, and 25% had elevated Ki-67 indices, indicating a higher proliferative index. Although ATRX mutations are rare in PitNETs, tumors with ATRX loss tend to be more aggressive and exhibit proliferative and transformative properties. Due to the limited number of cases, further studies with larger, prospective cohorts are needed to better understand the role of ATRX loss in PitNET progression and aggressiveness. Competing Interest Statement The authors have declared no competing interest. Funding Statement The author(s) received no specific funding for this work. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Inclusion of three new figures and introduction. Updated systematic review results up to March 2025. Additional edits and revisions for clarity and depth. Data Availability All relevant data are within the manuscript and its Supporting Information files.