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 corticotrophic 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.