Prognosis Of Adrenocortical Carcinoma Research Articles

CDH2 and CDH13 as potential prognostic and therapeutic targets for adrenocortical carcinoma

ABSTRACT Cadherin 2 (CDH2, N-cadherin) and cadherin 13 (CDH13, T-cadherin, H-cadherin) affect the progress and prognoses of many cancers. However, their roles in adrenocortical carcinoma (ACC), a rare endocrine cancer, remain unclear. To decipher the roles of these proteins in ACC and to identify their regulatory targets, we analyzed their expression levels, gene regulatory networks, prognostic value, and targets in ACC, using various bioinformatic analyses. CDH2 was strongly downregulated and CDH13 was strongly upregulated in patients with ACC; the expression levels of these genes affected the prognosis. In 75 patients, the expression of CDH2 and CDH13 was altered by 8% and 5%, respectively. CDH2 and CDH13, as well as their neighboring genes, were predicted to form a complex network of interactions, mainly through coexpression and physical and genetic interactions. CDH2 and its altered neighboring genes (ANGs) mainly affect tumor-related gene expression, cell cycle, and energy metabolism. The regulation of tumor-related integrin function, gene transcription, metabolism, and amide and phospholipid metabolism are the main functions of CDH13 and its ANGs. MiRNA and kinase targets of CDH2 and CDH13 in ACC were identified. CDH13 expression in patients with ACC was positively associated with immune cell infiltration. Anti-PD1/CTLA-4/PD-L1 immunotherapy significantly downregulated the expression of CDH13 in patients with ACC. Foretinib and elesclomol were predicted to exert strong inhibitory effects on SW13 cells by inhibiting the expression of CDH2 and CDH13. These data indicate that CDH2 and CDH13 are promising targets for precise treatment of ACC and may serve as new biomarkers for ACC prognosis.

Prognostic value of fibrinogen change value in adrenocortical carcinoma patients

PurposeThe aim was to explore the preoperative and postoperative fibrinogen changes value (FCV) as a prognosis biomarker for in patients with adrenocortical carcinoma (ACC).MethodsWe identified 42 patients with ACC and 190 patients with adrenal adenoma (AA) who underwent surgery at our institution between 2015 and 2023. Preoperative fibrinogen, postoperative fibrinogen and follow-up information of the patients were recorded and analysed. The relationship between FCV and overall survival (OS)/ relapse-free survival (RFS) was evaluated.ResultsThe mean level of preoperative and postoperative fibrinogen for ACC were 4.00 ± 1.64 g/L and 2.75 ± 0.59 g/L, respectively (p < 0.001). The mean level of preoperative and postoperative fibrinogen for AA were 2.79 ± 0.59 g/L and 2.71 ± 0.58 g/L, respectively (p = 0.144). In ACC, the lower FCV (≤ 1.25 g/L) showed a significantly poorer RFS than the higher (> 1.25 g/L) (p = 0.007); however, the lower FCV (≤ 1.25 g/L) showed no poorer OS than the higher (> 1.25 g/L) (p = 0.243). On multivariate survival analyses, FCV remained a predictor of RFS (HR 3.138).ConclusionAccording to the data in this study, it can be said that FCV is correlated with prognosis of ACC. The FCV might be a new biomarker for predicting the RFS of ACC.

A pan-cancer analysis unveiling the function of NR4A family genes in tumor immune microenvironment, prognosis, and drug response.

NR4A family genes play crucial roles in cancers. However, the role of NR4A family genes in cancers remains paradoxical as they promote or suppress tumorigenesis. We aimed to conduct comprehensive analyses of the association between the expression of NR4A family genes and tumor microenvironment (TME) based on bioinformatics methods. We collected RNA-seq data from 33 cancer types and 20 normal tissue sites from the TCGA and GTEx databases. Expression patterns of NR4A family genes and their associations with DNA methylation, miRNA, overall survival, drug responses, and tumor microenvironment were investigated. Significant downregulation of all NR4A family genes was observed in 15 cancer types. DNA promoter methylation and expression of NR4A family genes were negatively correlated in five cancers. The expression of 10 miRNAs targeting NR4A family genes was negatively correlated with the expression of NR4A family genes. High expression of all NR4A family genes was associated with poor prognosis in stomach adenocarcinoma and increased expressions of NR4A2 and NR4A3 were associated with poor prognosis in adrenocortical carcinoma. In addition, we found an elevated expression of NR4A2, which enhances the response to various chemotherapeutic drugs, whereas NR4A3 decreases drug sensitivity. Interestingly, in breast cancer, NR4A3 was significantly associated with C2 (IFN-γ dominant), C3 (inflammatory), and C6 (TGF-β dominant) immune subtypes and infiltrated immune cell types, implying both oncogenic and tumor-suppressive functions of NR4A3 in breast cancer. The NR4A family genes have the potential to serve as a diagnostic, prognostic, and immunological marker of human cancers.

Survival nomogram and risk classification system for patients with adrenocortical carcinoma: a study based on the SEER database and external validation in China.

Adrenocortical carcinoma (ACC) is an extremely rare and highly invasive malignant tumor. However, there is currently no reliable method to predict the prognosis of ACC. Our objective is to construct a nomogram and a risk classification system to predict the 1-year, 3-year, and 5-year overall survival (OS) of ACC. We retrieved clinicopathological data of patients diagnosed with ACC in The Surveillance, Epidemiology, and End Results (SEER) database and divided them into training and validation cohorts with a 7:3 ratio. Simultaneously, we collected an external validation cohort from The First Affiliated Hospital of Naval Medical University (Shanghai, China). Univariate and multivariate Cox analyses were performed to identify relevant risk factors, which were then combined to develop a correlation nomogram. The predictive performance of the nomogram was evaluated using the concordance index (C-index), receiver-operating characteristic curve (ROC), and calibration curves. Decision curve analysis (DCA) was applied to assess the clinical utility of the nomogram. In addition, Kaplan-Meier survival curves were generated to demonstrate the variation in OS between groups. The final nomogram consisted of five factors: age, T, N, M, and history of chemotherapy. Our prognostic model demonstrated significant discriminative ability, with C-index and the area under the receiver operating characteristic (AUC) values exceeding 0.70. Additionally, DCA validated the clinical utility of the nomogram. In the entire cohort, the median OS for patients in the low- and high-risk groups was 70 and 10 months, respectively. A nomogram and a corresponding risk classification system were developed in order to predict the OS of patients diagnosed with ACC. These tools have the potential to provide valuable support for patient counseling and assist in the decision-making process related to treatment options.

Comprehensive analysis of ADGRE5 gene in human tumors: Clinical relevance, prognostic implications, and potential for personalized immunotherapy

PurposeThe Adhesion G protein receptor E5 (ADGRE5) gene is involved in a wide range of biological functions in human tumors; however, its specific molecular mechanism and significance in the analysis of human tumors have not yet been determined. Here, we provide a comprehensive genomic architecture of ADGRE5 in the tumor immune microenvironment and its clinical relevance across a broad range of solid tumors. MethodsIn this study, we used publicly available bioinformatics databases, with a primary focus on The Cancer Genome Atlas (TCGA) database and GTEx data, to conduct a comprehensive analysis of the impact on patient prognosis associated with ADGRE5. ResultsStatistics of more than 30 solid tumors from TCGA and Cancer Cell Line Encyclopedia (CCLE) were examined. ADGRE5 was differentially expressed in several cancers and was significantly associated with survival outcomes. Higher ADGRE5 levels were associated with worse prognosis in adrenocortical carcinoma, low grade glioma of the brain (LGG), lung squamous cell carcinoma, liver hepatocellular carcinoma, and uveal melanoma (UVM). Additionally, ADGRE5 was found to be an independent risk factor for LGG and UVM. The clinical relevance of ADGRE5 in tumor immunogenicity was further investigated. The expression level of ADGRE5 was not only strongly associated with tumor infiltration, such as tumor-infiltrating immune cells and immune subtypes, but also with tumor mutation burden, pyroptosis, and epithelial-mesenchymal transition in various types of cancer (P < 0.05). Furthermore, we noted that ADGRE5 exhibited a positive association with targeted drug sensitivity and conversely, a negative association with traditional chemotherapeutic drug sensitivity. Thus, ADGRE5 is expected to be a guiding marker gene for clinical prognosis and personalized tumor immunotherapy.

Lamin B1: a novel biomarker in adult and pediatric adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis and high mortality rate. A high tumor mutational burden (TMB) has been found to be associated with poor prognosis in ACC. Thus, exploring ACC biomarkers based on TMB holds significant importance for patient risk stratification. In our research, we utilized weighted gene coexpression network analysis and an assay for transposase-accessible chromatin with high-throughput sequencing to identify genes associated with TMB. Through the comprehensive analysis of various public datasets, Lamin B1 (LMNB1) was identified as a biomarker associated with a high TMB and low chromatin accessibility. Immunohistochemical staining demonstrated high expression of LMNB1 in ACC compared to noncancerous tissues. Functional enrichment analyses revealed that the function of LMNB1 is associated with cell proliferation and division. Furthermore, cell assays suggested that LMNB1 promotes tumor proliferation and invasion. In addition, mutation analysis suggested that the high expression of LMNB1 is associated with TP53 mutations. Additionally, LMNB1 was highly expressed in the vast majority of solid tumors across cancers. In our immune analysis, we discovered that the high expression of LMNB1 might suppress the infiltration of CD8+ T cells in the ACC microenvironment. In summary, LMNB1 is a predictive factor for the poor prognosis of adult and pediatric ACC. Its high expression in ACC is positively associated with high TMB and lower chromatin accessibility, and it promotes ACC cell proliferation and invasion. Therefore, LMNB1 holds promise as a novel biomarker and potential therapeutic target for ACC.

Pan-cancer analysis of the role of α2C-adrenergic receptor (ADRA2C) in human tumors and validation in glioblastoma multiforme models.

Background: Several studies have reported the relationship between α2C-adrenergic receptor (ADRA2C) and both neoplastic and non-neoplastic diseases. However, a comprehensive pan-cancer analysis is currently lacking. Methods: Utilizing the RNA sequencing (RNA-seq) datasets from The Cancer Genome Atlas (TCGA) database, the roles of ADRA2C in human pan-cancer were analyzed through a variety of bioinformatics approaches, including R programming language and single-cell sequencing data analysis, et al. Besides, cell migration assay and immunochemistry were employed to further validate the role of ADRA2C in glioblastoma multiforme (GBM) cell lines and GBM mouse model. Results: A total of 33 cancer types were involved in this study. It was revealed that the expression level of ADRA2C varied across different clinical stages in patients with breast invasive carcinoma (BRCA), esophageal adenocarcinoma (ESCA), kidney renal papillary cell carcinoma (KIRP) and lung squamous cell carcinoma (LUSC). Meanwhile, it was found that ADRA2C may play roles in prognosis of adrenocortical carcinoma (ACC), glioblastoma multiforme and lower grade glioma (GBM-LGG), and uveal melanoma (UVM). Functional enrichment analysis suggested that ADRA2C expression level was highly correlated with neuronal system-related pathways. Moreover, ADRA2C may be a promising diagnostic marker for cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), GBM, GBMLGG, kidney chromophobe (KICH), and KIRP. Additionally, ADRA2C expression level was correlated with the levels of several infiltrating cells and immune checkpoint genes. Besides, the single-cell sequencing data analysis indicated that ADRA2C played a role in multiple tumor development processes in GBM, retinoblastoma (RB), and UVM. Finally, in vitro and in vivo experiments confirmed that the expression level of ADRA2C may be associated with glioma cell migration, apoptosis, and invasion. Conclusion: ADRA2C exhibited to play a notable role in several cancer types, suggesting that ADRA2C could serve as a promising biomarker or target for cancer diagnosis, prognosis, and treatment, particularly for GBM.

Identification of Key Genes and Related Drugs of Adrenocortical Carcinoma by Integrated Bioinformatics Analysis.

Adrenocortical carcinoma (ACC) is a malignant carcinoma with an extremely poor prognosis, and its pathogenesis remains to be understood to date, necessitating further investigation. This study aims to discover biomarkers and potential therapeutic agents for ACC through bioinformatics, enhancing clinical diagnosis and treatment strategies. Differentially expressed genes (DEGs) between ACC and normal adrenal cortex were screened out from the GSE19750 and GSE90713 datasets available in the GEO database. An online Venn diagram tool was utilized to identify the common DEGs between the two datasets. The identified DEGs were subjected to functional assessment, pathway enrichment, and identification of hub genes by performing the protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The differences in the expressions of hub genes between ACC and normal adrenal cortex were validated at the GEPIA2 website, and the association of these genes with the overall patient survival was also assessed. Finally, on the QuartataWeb website, drugs related to the identified hub genes were determined. A total of 114 DEGs, 10 hub genes, and 69 known drugs that could interact with these genes were identified. The GO and KEGG analyses revealed a close association of the identified DEGs with cellular signal transduction. The 10 hub genes identified were overexpressed in ACC, in addition to being significantly associated with adverse prognosis in ACC. Three genes and the associated known drugs were identified as potential targets for ACC treatment.

Validated predictive model for treatment and prognosis of adrenocortical carcinoma

BackgroundAdrenocortical carcinoma has a poor prognosis and multiple clinical, pathological, and treatment variables. Currently, we lack a prognostic and treatment calculator to determine the survival and efficacy of adjuvant chemoradiation. We aimed to validate a calculator to assess prognosis and treatment. MethodsWe searched the National Cancer Database to identify patients with adrenocortical carcinoma surgically treated from 2004 to 2020 and randomly allocated them into a training (80%) or validation set (20%). We analyzed the variables of age; sex; Charlson Comorbidity Index; insurance status; tumor size; pathologic tumor, node, and metastasis categories; surgical margins; and use of chemotherapy and radiation therapy. We used Cox regression prediction models and bootstrap coefficients to generate a mathematical model to predict 5- and 10-year overall survival. After using the area under the curve analysis to assess the model’s performance, we compared overall survival in the training and validation sets. ResultsMultivariable analysis of the 3,480 patients included in the study revealed that all variables were significant except sex (P < .05) and incorporated into a mathematical model. The area under the curve for 5- and 10-year overall survival was 0.68 and 0.70, respectively, for the training set and 0.70 and 0.72, respectively, for the validation set. For the bootstrap coefficients, the 5- and 10-year overall survival was 6.4% and 4.1%, respectively, above the observed mean. ConclusionOur model predicts the overall survival of patients with adrenocortical carcinoma based on clinical, pathologic, and treatment variables and can assist in individualizing treatment.

FRI222 Large Non-functional Adrenocortical Carcinoma In A Patient With History Of Occupational Radiation Exposure

Abstract Disclosure: A. Makawi: None. G. Elshimy: None. N. Martinez de Andino: None. A. Bolduc: None. Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.1-2.0 cases/per million per year. Up to 70% of tumors present with biochemically apparent adrenocortical hormone production. Diagnosis requires investigation of clinical, biological, and imaging features with measurement of steroid hormones key for evaluation. Anderson’s syndrome is commonly seen. Research has shown ACC is driven by several molecular changes that include the inactivation of tumor suppressor genes and activation of different oncogenes, DNA mutations, and epigenetic changes. The widely used staging of ACC is by the European Network of Study of Adrenal Tumors (ENSAT) as it is correlated with clinical outcomes. Here we present a case of a non-secretory ACC noted for 10 years with growth up to 7.5 cm in a patient with history of occupational radiation exposure. Case Presentation: Patient is a 57-year-old white male with history of colon polyps, basal and squamous cell carcinoma, and hypertension diagnosed 10 years prior, on amlodipine 5 mg and lisinopril 20 mg daily who presented to adrenal clinic for evaluation of a 7cm left adrenal mass that had grown from 1.8cm 10 years prior, to 5.7cm 7 years later to 7.5cm at time of surgery. He had symptoms of fatigue and occasional lightheadedness with no other signs or symptoms of Cushing's or pheochromocytoma. Family history noncontributory. He has a history of occupational exposure to radiation working at a nuclear reactor. Workup for adrenal incidentaloma included assays of serum normetanephrine which was increased at 1.2 nmol/L (reference &amp;lt;0.9 nmol/L) with normal metanephrine less than 0.20 nmol/L, normal DHEA-S of 52 mcg/dL, normal ACTH of 16 pg/mL and negative 1mg dexamethasone suppression test with serum cortisol suppressed to 0.78 mcg/dL. CT scan adrenal protocol showed a heterogeneous 7.7x6.6 cm left adrenal mass with 30 HU, with an absolute adrenal washout of 39% and relative washout of 31.4%. He then underwent left adrenalectomy on 12/16/2022. The tumor measured 7.5cm with pathology of low-grade ACC with staging of pT3. Margins were negative for carcinoma but microscopic angioinvasion and capsular invasion were noted. Postoperatively, the patient had resolution of his symptoms with marked improvement in BP. We continue to follow him in clinic for postoperative management. He has been referred for genetic testing with results pending. Discussion: The prognosis of ACC has been believed to be poor due to the low prevalence and sample size of ACC patients, but recent studies have shown that ACC presentation, survival, and prognosis are heterogeneous. Only 20-30% of ACC are nonfunctional. It is important to note that only 30% of ACC cases are curable at early stages, further impacting the poor prognosis. The goal of this report is to bring further attention to the timely assessment and personalized management of ACC given the evolving knowledge base. Presentation: Friday, June 16, 2023

Diagnostic and Prognostic Value of Neutrophil-Lymphocyte Ratio in Adrenocortical Carcinoma

BackgroundThe aim was to explore the value of neutrophil-lymphocyte ratio (NLR) as a biomarker for predicting the prognosis or diagnosis in adrenocortical carcinoma (ACC). MethodsWe identified 262 patients with adrenal gland disease who underwent operation at our institution between 2013 and 2018. According to postoperative pathology, patients were divided into 2 groups: ACC and non-ACC groups. The neutrophil and lymphocyte count of patients were recorded. Within the intergroup comparison, data obtained from ACC and non-ACC groups were evaluated using ANOVA test. The cut-off values of NLR for the prognosis in ACC were determined according to 3 methods. ResultsThe NLR values of ACC and non-ACC groups were 5.36 ± 5.30 and (1.73 ± 0.26) ∼ (2.56 ± 1.35), respectively (P < .001). NLR carry a differential property was evaluated with ROC curve to distinguish the above 2 groups. The cut-off value of NLR was estimated as 2.65 according to the Youden index. With this value, sensitivity was found as 67.5%, specificity was 83.8% and AUC was 0.749 (P < .001, confidence interval = 0.638-0.860). In ACC, the higher NLR group was not shown significantly poorer overall survival than the lower NLR group (NLR ≥2.65 vs. NLR < 2.65, NLR ≥5 vs. NLR <5, NLR ≥5.36 vs. NLR <5.36) (P > .05). ConclusionAccording to the data in this study, it can be said that adrenocortical tumors are likely to be malignant by 67.5% if the NLR value is greater than 2.65. When we use the NLR to predict the prognosis of ACC, there is not statistically significant.

Identification of the ferroptosis regulator HELLS with prognostic value for adrenocortical carcinoma based on integrated analysis and experimental validation.

For adrenocortical carcinoma (ACC), a rare endocrine malignancy with a high rate of mortality and recurrence, it is difficult for clinicians to predict overall survival and select the most effective treatment. Targeting ferroptosis, a form of cell death, has been reported to be a promising therapeutic strategy for ACC; however, the core ferroptosis regulator and its prognostic value in ACC remain unknown. RNA sequencing data and clinical information were downloaded from public databases. Differentially expressed gene and survival analyses were performed to identify candidate ferroptosis regulators. A multivariate Cox regression model was used to construct a gene signature, and a nomogram was constructed to predict the overall survival of patients with ACC. Gene set variation analysis (GSVA) was used to identify underlying aberrant pathways and the relative immune cell infiltration levels of each ACC sample. Immunohistochemistry staining was performed in formalin-fixed paraffin-embedded tumor tissue sections. Ultimately, 23 differentially expressed ferroptosis regulators were identified between normal adrenal gland and ACC tissues, and 50 ferroptosis regulators were related to prognosis, with 13 ferroptosis regulators being simultaneously found to satisfy the differential expression and prognostic value. According to the multivariate Cox regression model, a ferroptosis regulator signature was constructed from 3 genes in The Cancer Genome Atlas (TCGA; hazard ratio =9.01; P=1.39×10-10), and the area under the curve (AUC) values of 3-, 5-, 8-year overall survival were 0.924, 0.906, and 0.866, respectively. The survival analysis and the receiver operating characteristic (ROC) analysis validated the prognostic value of the ferroptosis regulator signature in 3 validation datasets. Moreover, metabolism-, E2F-, MYC-, and G2/M checkpoint-related pathways and aberrant immune cell infiltration levels were identified as being responsible for the different prognosis of risk groups in ACC. HELLS was found to be a significantly differentially expressed ferroptosis-suppressor gene with a prognostic value in ACC and to be highly associated with immune cell infiltration levels and multiple biological functions. A ferroptosis regulator signature showed promising power for predicting the prognosis of ACC, and HELLS was identified as a hub ferroptosis regulator in the initiation and progression of ACC.

A Clinicopathological Analysis of Asian Patients with Adrenocortical Carcinoma: A Single-Center Experience

There is limited information regarding the immunohistochemistry stain and its prognostic role in adrenocortical carcinoma (ACC), and few studies focus on Asian patients. Our study aims to identify the correlation between immunohistochemistry staining and the prognosis of ACC in Asian patients. We searched the database of a single center in Taiwan for cases with a pathological diagnosis of ACC in the past 25 years. We collected patient data on age, sex, initial presentation, staging, metastatic site, and survival duration. Immunohistochemical studies using antibodies to CDK4, ATRX, beta-catenin, Ki-67, SSTR2, and p53 were performed. Survival analysis was performed using the log-rank test, the Cox proportional hazards model and bootstrapping with 5000 samplings. Fourteen patients were identified, and the median age was 49.5 (range 1-70) years. There were eight male and six female patients. Four patients presented with Cushing's syndrome, and half were diagnosed with stage IV ACC at presentation. Only three patients survived (21%). The median survival time was 15.5 (range 0.67-244) months. SSTR2 expression score > 50 (log-rank test: p = 0.009) and Ki-67 > 50% (log-rank test: p = 0.017) were associated with mortality. However, after adjusting for stage, the bootstrapping analysis demonstrated that Ki-67 [B 2.04, p = 0.004], Beta-catenin [B 2.19, p = 0.009], ATRX [B 1.48, p = 0.026], P53 [B 1.58, p = 0.027], SSTR2 [B 1.58, p = 0.015] and SSTR2 expression score [B 0.03, p < 0.001] were all significantly associated with mortality. After adjusting for stage, Ki-67 > 50%, Beta-catenin, ATRX, P53, SSTR2 and SSTR2 expression score > 50 were associated with mortality in Asian patients with ACC.

Prognostic predictors of adrenocortical carcinoma: A single-center thirty-year experience.

The prognosis of adrenocortical carcinoma (ACC) is poor but highly variable. The present study aimed to characterize patients with ACC at a single center in Taiwan and to determine the prognostic predictors of overall and progression-free survival. Medical records of patients, who were diagnosed with ACC at Taipei Veterans General Hospital between January 1992 and June 2021, were reviewed. Patient demographics, tumor characteristics, and subsequent treatment were analyzed with regard to overall survival and progression-free survival using Kaplan-Meier methods and a Cox regression model. Sixty-seven patients were included. Females (65.7%) were more susceptible to ACC, with a younger onset and active hormonal secretion. One-half of the patients exhibited distant metastases at the time of diagnosis. The European Network for the Study of Adrenal Tumours (ENSAT) stage (hazard ratio [HR] 3.60 [95% confidence interval (CI) 1.25-10.38]; p=0.018), large vessel invasion (HR 5.19 [95% CI 1.75-15.37]; p=0.003), and mitotane use (HR 0.27 [95% CI 0.11-0.70]; p=0.007) were significantly associated with overall survival (OS). There was no single factor independently associated with progression-free survival. ENSAT stage had a substantial impact on overall survival though there was no difference in OS between patients with stage II and stage III ACC. Large vessel invasion portended poor prognosis and influenced OS significantly. Moreover, mitotane only improved clinical outcomes of patients with stage IV disease.

The signature of pyroptosis-related gene prognostic and immune microenvironment in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) has a low incidence but a poor prognosis. And ACC has complex clinical manifestations and limited treatment. Pyroptosis has a dual character and has both positive and negative effects on cancer. However, the role of pyroptosis-related genes (PRGs) in ACC and the impact on ACC progression remains unelucidated. This study performed systematic bioinformatics analysis and basic experimental validation to enable the establishment of prognostic models and demonstrate levels of immune infiltration. Pearson's correlation analysis was used to assess the association of PRGs with tumor immune infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoints. There 4 PRGs were upregulated, and 25 PRGs were downregulated in ACC. At the same time, we analyzed and reviewed the genetic mutation variation landscape of PRGs. Functional enrichment analysis was also performed to clarify the function of PRGs. Pyroptosis, the inflammatory response, the Toll-like receptor signaling pathway, and the NOD-like receptor signaling pathway are the functions and pathways mainly involved and exerted effects by these 33 PRGs. The results of the prognosis analysis revealed high expression of CASP3, CASP9, GSDMB, GSDMD, NLRC4, PRKACA, and SCAF11 caused a poor survival rate for ACC patients. The above seven PRGs were screened by the optimal λ value of LASSO Cox analysis, and the five selected genes (CASP3, CASP9, GSDMB, GSDMD, NLRC4) were involved in constructing a prognostic PRGs model which enables the overall survival in ACC patients can be predicted with moderate to high accuracy. Prognostic PRGs, especially CASP9, which is the independent factor of ACC prognosis, may be closely correlated with immune-cell infiltration, tumor mutation burden, microsatellite instability, and immune checkpoints. Quantitative Real-Time PCR (qRT-PCR), Western blot and immunohistochemical were performed to validate the mRNA expression levels of CASP9 in adjacent normal tissues and ACC tissues. According to the result of immune checkpoints analysis, NLRC4 and GSDMB may be identified as potential therapeutic targets. In conclusion, we established a prognostic model of PRG characteristics in ACC and analyzed the relationship between PRGs and immune infiltration. Through our study, it may be helpful to find the mechanism of pyroptosis in ACC.

Pan-Cancer Analysis of Histone Methyltransferase KMT2D with Potential Implications for Prognosis and Immunotherapy in Human Cancer.

Pan-cancer analysis is an efficient tool to obtain a panoramic view of cancer- related genes and identify their oncogenic processes, facilitating the development of new therapeutic targets. Lysine methyltransferase 2D (KMT2D), acting as a major enhancer coactivator for mammalian cells, is one of the most frequently mutated genes across various cancer types and is considered an oncogene and a rationale for epigenetic therapeutic targets. This study was designed to explore the potential role of KMT2D in human cancer through a pan-cancer analysis. The expression of KMT2D was assessed in normal tissues and cell lines, and pancancers from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTE) datasets were used to explore its correlation with prognosis, immune cell infiltration, tumor mutation burden, microsatellite instability, and mismatch repair. KMT2D expression was heterogeneous across different cancer types. Increased KMT2D indicated a worse prognosis in adrenocortical carcinoma (ACC), brain lower-grade glioma (LGG), and mesothelioma (MESO), while patients with high KMT2D expression showed better outcomes in renal clear cell carcinoma (KIRC). Moreover, KMT2D expression was positively correlated with immune cell infiltration and negative tumor mutation burden in multiple cancers. In addition, a significant correlation between KMT2D and immune checkpoint-related genes or mismatch repair genes was identified. These findings support the hypothesis that KMT2D is not only a potential biomarker for prognosis and immunotherapy response prediction but also an essential immune regulator in human cancer.

Ferroptosis Biomarkers for Predicting Prognosis and Immunotherapy Efficacy in Adrenocortical Carcinoma

Numerous studies have suggested that ferroptosis plays an important regulatory role in cancer cell death. Nonetheless, the potential effects of ferroptosis regulators on the prognosis, the expression of immunomodulatory factors in the tumor microenvironment and on the efficacy of immunotherapy in adrenocortical carcinoma (ACC) remain largely unknown. Public ACC datasets were used to investigate the relationship between ferroptosis regulators and prognosis and clinical features. A ferroptosis scoring system was established for individual cases of ACC using principal component analysis algorithms. Hub ferroptosis-related genes involved in immunoregulation and immunotherapy efficacy in ACC were further identified. Twenty ferroptosis regulators were differentially expressed in ACC and 17 ferroptosis regulators were closely related to prognosis in ACC. A ferroptosis scoring system was developed based on ACSL4, FANCD2, and SLC7A1 expression, and the ferroptosis regulators could serve as an independent prognostic factor for ACC. Further analyses indicated that the ferroptosis score integrated with the tumor mutation burden (TMB), and immune-checkpoint gene expression could predict prognosis in ACC. RNA isolation and reverse transcription‑quantitative polymerase chain reaction (RT-qPCR) demonstrated significant differences in the expression levels of ACSL4, FANCD2, and SLC7A1 between ACC and normal tissues. Furthermore, FANCD2 was significantly related to immunotherapy efficacy and prognosis in ACC. Our study demonstrated that ferroptosis was significantly associated with prognosis, clinical characteristics, immune-checkpoint gene expression, and tumor microenvironment immune cell infiltration in ACC. The current study provides comprehensive evidence for further research on ferroptosis regulators in ACC and provides new insight into the epigenetic regulation of the antitumor immune response.

Spindle and Kinetochore-Associated Complex Is Associated With Poor Prognosis in Adrenocortical Carcinoma.

The spindle and kinetochore-associated (SKA) complex, composed of three subunits (SKA1, SKA2, and SKA3), stabilizes spindle microtubule attachment to the kinetochore (KT) in the middle stage of mitosis. High expression of this complex is associated with poor prognosis for several tumors. However, the potential role of SKA complex overexpression in rare malignant diseases, such as adrenocortical carcinoma (ACC), has not been well investigated. In this study, we used several databases to explore the relationship between SKA subunit expression and prognosis in ACC patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) databases were used to analyze enriched pathways in ACC. The results suggest that each of the three SKA subunits are overexpressed in ACC and that high expression is correlated with poor patient prognosis. Overexpression of the SKA complex is associated with the expression of organelle fission, nuclear division, and chromosome segregation pathways. Furthermore, differential expression of hub genes for proteins that interact physically or functionally with the SKA complex (CCNB2, UBE2C, BUB1B, TPX2, CCNA2, CDCA8, CCNB1, MELK, TOP2A, and KIF2C) revealed additional potential biomarkers for ACC. Our findings provide additional understanding of the mechanisms of ACC and suggest an approach for biomarker discovery using publicly available resources.

Identification of a chromatin regulator signature and potential prognostic ability for adrenocortical carcinoma.

Objective: Adrenocortical carcinoma (ACC) is a rare malignant tumor. Chromatin regulators (CRs) can drive epigenetic changes, which have been considered as one of the most vital hallmarks of tumors. This study aimed to explore the CR signature for ACC in order to clarify the molecular basis of ACC’s pathogenic mechanism and provide novel methods to diagnose and treat ACC clinically. Methods: This study obtained transcriptome sequencing datasets of ACC patients and sequencing data on normal adrenal tissues in TCGA and GTEx databases, respectively. Meanwhile, prognostic genes were selected through Lasso and Cox regression analyses. Using the transcriptome sequencing datasets of ACC patients downloaded from the GEO database to finish validation, we performed Kaplan–Meier (KM) analysis for evaluating the differential survival between low- and high-risk groups. Then, this work constructed the risk model for predicting ACC prognosis. TIMER 2.0 was employed to assess the differences in immune infiltration between the two groups. Furthermore, this work adopted the R package “pRRophetic” for exploring and estimating the sensitivity of patients to different chemotherapeutic agents. Results: A 5-CR model was established to predict ACC survival, and the CR signature was confirmed as a factor in order to independently predict ACC patient prognosis. In addition, a nomogram composed of the risk score and clinical T stage performed well in the prediction of patients’ prognosis. Differentially expressed CRs (DECRs) were mostly associated with the cell cycle, base excision repair, colon cancer, gene duplication, homologous recombination, and other signaling pathways for the high-risk group. As for the low-risk group, DECRs were mainly enriched in allograft rejection, drug metabolism of cytochrome P450, metabolism of xenogeneic organisms by cytochrome P450, retinol metabolism, and other signaling pathways. According to TIMER analysis, the immune infiltration degrees of endothelial cells, M2 macrophages, myeloid dendritic cells, CD4+ Th1 cells, NKT cells, and M0 macrophages showed significant statistical differences between the high- and low-risk groups, and high infiltration levels of M0 and M2 macrophages were more pronounced in higher T stage (T3 and T4), N stage (N1), and clinical stages (III and IV). In addition, high-risk cases exhibited higher sensitivity to etoposide and doxorubicin. Additionally, low-risk patients had significantly decreased expression of RRM1 compared with high-risk cases, suggesting the better effect of mitotane treatment. Conclusion: This study identified the DECRs, which might be related to ACC genesis and progression. The pathways enriched by these DECRs were screened, and these DECRs were verified with excellent significance for estimating ACC survival. Drug sensitivity analysis also supported the current clinical treatment plan. Moreover, this study will provide reliable ideas and evidence for diagnosing and treating ACC in the clinic.

Pan-cancer analysis of necroptosis-related gene signature for the identification of prognosis and immune significance

BackgroundNecroptosis is a novel programmed cell death mode independent on caspase. A number of studies have revealed that the induction of necroptosis could act as an alternative therapeutic strategy for drug-resistant tumors as well as affect tumor immune microenvironment.MethodsGene expression profiles and clinical data were downloaded from XENA-UCSC (including The Cancer Genome Atlas and Genotype-Tissue Expression), Gene Expression Omnibus, International Cancer Genome Consortium and Chinese Glioma Genome Atlas. We used non-negative matrix factorization method to conduct tumor classification. The least absolute shrinkage and selection operator regression was applied to establish risk models, whose prognostic effectiveness was examined in both training and testing sets with Kaplan–Meier analysis, time-dependent receiver operating characteristic curves as well as uni- and multi-variate survival analysis. Principal Component Analysis, t-distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection were conducted to check the risk group distribution. Gene Set Enrichment Analyses, immune infiltration analysis based on CIBERSORT, EPIC, MCPcounter, ssGSEA and ESTIMATE, gene mutation and drug sensitivity between the risk groups were also taken into consideration.ResultsThere were eight types of cancer with at least ten differentially expressed necroptosis-related genes which could influence patients’ prognosis, namely, adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pancreatic adenocarcinoma (PAAD), liver hepatocellular carcinoma (LIHC), skin cutaneous melanoma (SKCM) and thymoma (THYM). Patients could be divided into different clusters with distinct overall survival in all cancers above except for LIHC. The risk models could efficiently predict prognosis of ACC, LAML, LGG, LIHC, SKCM and THYM patients. LGG patients from high-risk group had a higher infiltration level of M2 macrophages and cancer-associated fibroblasts. There were more CD8+ T cells, Th1 cells and M1 macrophages in low-risk SKCM patients’ tumor microenvironment. Gene mutation status and drug sensitivity are also different between low- and high-risk groups in the six cancers.ConclusionsNecroptosis-related genes can predict clinical outcomes of ACC, LAML, LGG, LIHC, SKCM and THYM patients and help to distinguish immune infiltration status for LGG and SKCM.