Explore the vast range of titles available.

Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1 , a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene ( SMARCB1 ), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10 −6 ). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma. Skull base chordomas are treated with surgery and chemotherapy but often recur due to incomplete resection, understanding the molecular underpinnings of the tumours may provide additional therapeutic strategies. Here, the authors carry out whole genome sequencing of 80 skull base chordoma tumours and identify the SWI/SNF component—PBRM1—as a frequently mutated gene.

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 ( SF3B1 R625H ) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels ( p  = 0.02) and shorter progression-free survival (PFS) ( p  = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1 R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics. The genetic basis of prolactinomas remains poorly understood. Here, the authors find a recurrent hotspot somatic mutation in the splicing factor 3 subunit B1 ( SF3B1 R625H ) in prolactinomas, and show that this mutation causes aberrant splicing of ESRRG mRNA leading to up-regulation of prolactin.

PurposeTo make individualised preoperative prediction of non-functioning pituitary adenoma (NFPAs) subtypes between null cell adenomas (NCAs) and other subtypes using a radiomics approach.MethodsWe enrolled 112 patients (training set: n = 75; test set: n = 37) with complete T1-weighted magnetic resonance imaging (MRI) and contrast-enhanced T1-weighted MRI (CE-T1). A total of 1482 quantitative imaging features were extracted from T1 and CE-T1 images. Support vector machine trained a predictive model that was validated using a receiver operating characteristics (ROC) analysis on an independent test set. Moreover, a nomogram was constructed incorporating clinical characteristics and the radiomics signature for individual prediction.ResultsT1 image features yielded area under the curve (AUC) values of 0.8314 and 0.8042 for the training and test sets, respectively, while CE-T1 image features provided no additional contribution to the predictive model. The nomogram incorporating sex and the T1 radiomics signature yielded good calibration in the training and test sets (concordance index (CI) = 0.854 and 0.857, respectively).ConclusionThis study focused on the preoperative prediction of NFPA subtypes between NCAs and others using a radiomics approach. The developed model yielded good performance, indicating that radiomics had good potential for the preoperative diagnosis of NFPAs.Key points• MRI may help in the pre-operative diagnosis of NFPAs subtypes• Retrospective study showed T1-weighted MRI more useful than CE-T1 in NCAs diagnosis• Treatment decision making becomes more individualised• Radiomics approach had potential for classification of NFPAs

Pituitary neuroendocrine tumors (PitNETs) are one of the most common intracranial tumors with diverse clinical manifestations. Current pathological classification systems rely primarily on histological hormone staining and transcription factors (TFs) expression. While effective in identifying three major lineages, molecular characteristics based on hormones and TFs lack sufficient resolution to fully capture the complex tumor heterogeneity. Transcriptional diversity by alternative splicing (AS) offered additional insight to address this challenge. Here, we perform bulk and full-length single-cell RNA sequencing to comprehensively investigate AS dysregulation across all PitNET lineages. We reveal pervasive splicing dysregulations that better depict tumor heterogeneity. Additionally, we delineate fundamental splicing heterogeneity at single-cell resolution, confirming bulk findings and refining splicing dysregulation varying among tumor cell types. Notably, we effectively distinguish the silent corticotroph subtype and define a distinct TPIT lineage subtype, which is associated with worse clinical outcomes and increased splicing abnormalities driven by altered ESRP1 expression. In conclusion, our results characterize the subtype specific AS landscape in PitNETs, enhancing the understanding of the PitNETs subtyping. Current classification systems of pituitary neuroendocrine tumors (PitNETs) rely on histological hormone staining and transcription factors. Here, the authors analyze alternative splicing at bulk and single-cell resolution in PitNETs, revealing additional subtypes associated with worse clinical outcomes and splicing abnormalities.

Background Pituitary neuroendocrine tumors (PitNETs) are one of the most common types of intracranial tumors. Currently, the cellular characteristics of normal pituitary and various other types of PitNETs are still not completely understood. Methods We performed single-cell RNA sequencing (scRNA-seq) on 4 normal samples and 24 PitNET samples for comprehensive bioinformatics analysis. Findings regarding the function of PBK in the aggressive tumor cells were validated by siRNA knockdown, overexpression, and transwell experiments. Results We first constructed a reference cell atlas of the human pituitary. Subsequent scRNA-seq analysis of PitNET samples, representing major tumor subtypes, shed light on the intrinsic cellular heterogeneities of the tumor cells and tumor microenvironment (TME). We found that the expression of hormone-encoding genes defined the major variations of the PIT1-lineage tumor cell transcriptomic heterogeneities. A sub-population of TPIT-lineage tumor cells highly expressing GZMK suggested a novel subtype of corticotroph tumors. In immune cells, we found two clusters of tumor-associated macrophages, which were both highly enriched in PitNETs but with distinct functional characteristics. In PitNETs, the stress response pathway was significantly activated in T cells. While a majority of these tumors are benign, our study unveils a common existence of aggressive tumor cells in the studied samples, which highly express a set of malignant signature genes. The following functional experiments confirmed the oncogenic role of selected up-regulated genes. The over-expression of PBK could promote both tumor cell proliferation and migration, and it was also significantly associated with poor prognosis in PitNET patients. Conclusions Our data and analysis manifested the basic cell types in the normal pituitary and inherent heterogeneity of PitNETs, identified several features of the tumor immune microenvironments, and found a novel epithelial cell sub-population with aggressive signatures across all the studied cases.

Purpose Sodium imbalance are common complications after transsphenoidal surgery (TSS) for pituitary neuroendocrine tumors (PitNETs). We characterized the types of sodium imbalance, identified risk factors for these disorders, and provided corresponding treatment advice. Methods We screened patients who had undergone TSS for PitNETs at a single center to identify those who did and did not (control) develop sodium imbalance. Disorders were classified using three groups, based mainly on the serum sodium level and degree of daily increase or decrease therein. We performed multivariable logistic regression analysis to identify risk factors among numerous variables (patient characteristics, third ventricle deformation, tumor volume, maximum tumor diameter, hydrocephalus, cerebrospinal fluid rhinorrhea, and pituitary target gland axes). Results The sample comprised 105 patients with and 129 patients without sodium imbalance. Logistic regression analysis showed that hydrocephalus [ P  = 0.0015, odds ratio (OR) = 7.112, 95% confidence interval (CI) 1.475–34.3], cerebrospinal fluid rhinorrhea ( P  < 0.001, OR = 4.62, 95% CI 2.372–9), and preoperative hypothalamus–pituitary–gonadal (HPG) axis hypofunction ( P  = 0.009, OR = 3.211, 95% CI 1.341–7.691) were independent risk factors sodium imbalance development after TSS. Compared with the control, risk factors differed among disorder groups. Conclusion This study showed that cerebrospinal fluid rhinorrhea, hydrocephalus, and preoperative HPG axis hypofunction are risk factors for sodium imbalance development after TSS for PitNETs. We divided sodium imbalances into three groups to guide treatment.

Background Bone-invasive Pituitary Neuroendocrine Tumors (BI PitNETs) epitomize an aggressive subtype of pituitary tumors characterized by bone invasion, culminating in extensive skull base bone destruction and fragmentation. This infiltration poses a significant surgical risk due to potential damage to vital nerves and arteries. However, the mechanisms underlying bone invasion caused by PitNETs remain elusive, and effective interventions for PitNET-induced bone invasion are lacking in clinical practice. Methods In this study, we performed single-cell ( n  = 87,287) RNA sequencing on 10 cases of bone-invasive PitNETs and 5 cases of non-bone-invasion PitNETs (Non-BI PitNETs). We identified various cell types and determined their interactions through cell-cell communication analysis, which was further validated experimentally. Results We identified a novel TNF-α + TAM macrophage subset. BI PitNETs showed increased IL-34 secretion, impacting TNF-α + TAMs via the IL34/CSF1R axis, leading to TNF-α production. TNF-α + TAMs, in turn, communicate with CD14 + monocytes to promote their differentiation into osteoclasts and leading to bone invasion. In addition, we defined a gene signature for TNF-α + TAM to guide the clinical prognosis prediction of BI PitNETs. Conclusions Our study elucidates the tumor microenvironment changes in bone invasion and identifies the critical role of TNF-α + TAMs in promoting bone invasion of PitNETs, laying a foundation for developing new molecular markers or therapeutic agents targeting BI PitNETs.

Background Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 ( SF3B1 R625H ), but its functional effects and underlying molecular mechanisms remain largely unexplored. Methods Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1 R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1 -wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1 R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA. Results Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1 R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1 R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1 R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway. Conclusions Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1 R625H mutation.

Background and Objectives: The diagnosis and treatment of pituitary adenomas with cavernous sinus invasion pose significant challenges for clinicians. The objective of this study is to investigate the expression profile and prognostic value of HSPB1 (heat shock protein beta-1) in pituitary adenomas with invasive and non-invasive features. Additionally, we aim to explore the potential relationship between HSPB1 expression and immunological functions in pituitary adenoma. Materials and Methods: A total of 159 pituitary adenoma specimens (73 invasive tumours and 86 non-invasive tumours) underwent whole-transcriptome sequencing. Differentially expressed genes and pathways in invasive and non-invasive tumours were analysed. HSPB1 was subjected to adequate bioinformatics analysis using various databases such as TIMER, Xiantao and TISIDB. We investigated the correlation between HSPB1 expression and immune infiltration in cancers and predicted the target drug of HSPB1 using the TISIDB database. Results: HSPB1 expression was upregulated in invasive pituitary adenomas and affected immune cell infiltration. HSPB1 was significantly highly expressed in most tumours compared to normal tissues. High expression of HSPB1 was significantly associated with poorer overall survival. HSPB1 was involved in the regulation of the immune system in most cancers. The drugs DB11638, DB06094 and DB12695 could act as inhibitors of HSPB1. Conclusions: HSPB1 may serve as an important marker for invasive pituitary adenomas and promote tumour progression by modulating the immune system. Inhibitors of HSPB1 expression are currently available, making it a potential target for therapy in invasive pituitary adenoma.

Background Tumor surrounding the internal carotid artery or invading to the cavernous sinus is an important characteristic of invasive pituitary adenoma, and a pivotal factor of tumor residue and regrowth. Without specific changes in serum hormone related to the adenohypophyseal cell of origin, clinically non-functioning pituitary adenoma is more likely to be diagnosed at invasive stages compared with functioning pituitary adenoma. The underlying mechanism of tumor invasion remains unknown. In this study, we aimed to identify key genes in tumor invasion by integrating analyses of DNA methylation and gene expression profiles. Method Genome-wide DNA methylation and mRNA microarray analysis were performed for tumor samples from 68 patients at the Beijing Tiantan Hospital. Differentially expressed genes and methylated probes were identified based on an invasive vs non-invasive grouping. Differentially methylated probes in the promoter region of targeted genes were assessed. Pearson correlation analysis was used to identify genes with a strong association between DNA methylation status and expression levels. Pyrosequencing and RT-PCR were used to validate the methylation status and expression levels of candidate genes, respectively. Results A total of 8842 differentially methylated probes, located on 4582 genes, and 661 differentially expressed genes were identified. Both promoter methylation and expression alterations were observed for 115 genes with 58 genes showing a negative correlation between DNA methylation status and expression level. Nineteen genes that exhibited notably negative correlations between DNA methylation and gene expression levels, are involved in various gene ontologies and pathways, or played an important role in different diseases, were regarded as candidate genes. We found an increased methylation with a decreased expression of PHYHD1, LTBR, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6, and a decreased methylation with an increased expression of MYBPHL. The methylation status and expression levels of these genes were validated by pyrosequencing and RT-PCR. Conclusions The DNA methylation and expression levels of PHYHD1, LTBR, MYBPHL, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6 are associated with tumor invasion, and these genes may become the potential genes for targeted therapy.