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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Biomarcadores de Tumor , Humanos , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/metabolismo , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/inmunología , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/inmunología , Biomarcadores de Tumor/metabolismo , Antígeno Ki-67/metabolismo , beta Catenina/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Invasividad Neoplásica , Inmunofenotipificación , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Nucleares/metabolismoRESUMEN
Aldosterone-producing adenoma is a subtype of primary aldosteronism. Recent advancements in multi-omics research have led to significant progress in understanding primary aldosteronism at the genetic level. Among the various genes associated with the development of aldosterone-producing adenomas, the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene has received considerable attention due to its prevalence as the most common somatic mutation gene in primary aldosteronism. This paper aims to integrate the existing evidence on the involvement of KCNJ5 gene in the pathogenesis of aldosterone-producing adenomas, to enhance the understanding of the underlying mechanisms of aldosterone-producing adenomas from the perspective of genetics, and to provide novel insights for the clinical diagnosis and treatment of aldosterone-producing adenomas.
Asunto(s)
Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Aldosterona , Canales de Potasio Rectificados Internamente Asociados a la Proteína G , Hiperaldosteronismo , Humanos , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Aldosterona/metabolismo , Aldosterona/biosíntesis , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Adenoma/genética , Adenoma/metabolismo , MutaciónRESUMEN
The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular-endothelial cells and cortical-neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/ß-catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single-nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma-specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal-related pathologies.
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Glándulas Suprarrenales , Homeostasis , Transcriptoma , Humanos , Transcriptoma/genética , Glándulas Suprarrenales/metabolismo , Homeostasis/genética , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Adulto , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/patologíaRESUMEN
BACKGROUND: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy. CASE PRESENTATION: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings. CONCLUSION: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.
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Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Aldosterona , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico , Hidrocortisona , Mutación , Complicaciones Neoplásicas del Embarazo , Humanos , Femenino , Embarazo , Adulto , Hidrocortisona/metabolismo , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/patología , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/cirugía , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Complicaciones Neoplásicas del Embarazo/genética , Complicaciones Neoplásicas del Embarazo/patología , Hiperaldosteronismo/genética , Hiperaldosteronismo/patología , Hiperaldosteronismo/cirugía , Síndrome de Cushing/genética , Síndrome de Cushing/patología , Adenoma/genética , Adenoma/patología , Adenoma/metabolismoRESUMEN
OBJECTIVE: To develop and validate a nomogram combining radiomics and pathology features to distinguish between aldosterone-producing adenomas (APAs) and nonfunctional adrenal adenomas (NF-AAs). METHODS: Consecutive patients diagnosed with adrenal adenomas via computed tomography (CT) or pathologic analysis between January 2011 and November 2022 were eligible for inclusion in this retrospective study. CT images and hematoxylin & eosin-stained slides were used for annotation and feature extraction. The selected radiomics and pathology features were used to develop a risk model using various machine learning models, and the area under the receiver operating characteristic curve (AUC) was determined to evaluate diagnostic performance. The predicted results from radiomics and pathology features were combined and visualized using a nomogram. RESULTS: A total of 211 patients (APAs, n = 59; NF-AAs, n = 152) were included in this study, with patients randomly divided into either the training set or the testing set at a ratio of 8:2. The ExtraTrees model yielded a sensitivity of 0.818, a specificity of 0.733, and an accuracy of 0.756 (AUC = 0.817; 95% confidence interval [CI]: 0.675-0.958) in the radiomics testing set and a sensitivity of 0.999, a specificity of 0.842, and an accuracy of 0.867 (AUC = 0.905, 95% CI: 0.792-1.000) in the pathology testing set. A nomogram combining radiomics and pathology features demonstrated a strong performance (AUC = 0.912; 95% CI: 0.807-1.000). CONCLUSION: A nomogram combining radiomics and pathology features demonstrated strong predictive accuracy and discrimination capability. This model may help clinicians to distinguish between APAs and NF-AAs.
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Neoplasias de las Glándulas Suprarrenales , Aldosterona , Humanos , Femenino , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Adulto , Aldosterona/metabolismo , Aldosterona/sangre , Diagnóstico Diferencial , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , Anciano , Tomografía Computarizada por Rayos X , Adenoma Corticosuprarrenal/diagnóstico por imagen , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Nomogramas , Adenoma/diagnóstico por imagen , Adenoma/patología , Adenoma/metabolismo , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Sensibilidad y Especificidad , Imagen Multimodal/métodosRESUMEN
CONTEXT: The search for somatic mutations in adrenals resected from patients with primary aldosteronism (PA) is performed by Sanger sequencing, often implemented with immunohistochemistry (IHC)-guidance focused on aldosterone-producing (CYP11B2-positive) areas. OBJECTIVE: To investigate the impact of double IHC for CYP11B1 and CYP11B2 on Sanger and next-generation sequencing (NGS). METHODS: We investigated 127 consecutive adrenal aldosterone-producing adenomas from consenting surgically cured PA patients using double IHC for CYP11B1 and CYP11B2, by Sanger sequencing and NGS. RESULTS: Double IHC for CYP11B2 and CYP11B1 revealed 3 distinct patterns: CYP11B2-positive adenoma (pattern 1), mixed CYP11B1/CYP11B2-positive adenoma (pattern 2), and adrenals with multiple small CYP11B2-positive nodules (pattern 3). Sanger sequencing allowed detection of KCNJ5 mutations in 44% of the adrenals; NGS revealed such mutations in 10% of those negative at Sanger and additional mutations in 61% of the cases. Importantly the rate of KCNJ5 mutations differed across patterns: 17.8% in pattern 1, 71.4% in pattern 2, and 10.7% in pattern 3 (χ2 = 22.492, P < .001). CONCLUSION: NGS allowed detection of mutations in many adrenals that tested negative at Sanger sequencing. Moreover, the different distribution of KCNJ5 mutations across IHC patterns indicates that IHC-guided sequencing protocols selecting CYP11B2-positive areas could furnish results that might not be representative of the entire mutational status of the excised adrenal, which is important at a time when KCNJ5 mutations are suggested to drive management of patients with aldosterone-producing adenomas.
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Citocromo P-450 CYP11B2 , Canales de Potasio Rectificados Internamente Asociados a la Proteína G , Hiperaldosteronismo , Inmunohistoquímica , Mutación , Esteroide 11-beta-Hidroxilasa , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 11-beta-Hidroxilasa/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Adulto , Secuenciación de Nucleótidos de Alto Rendimiento , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Adenoma Corticosuprarrenal/diagnóstico , Anciano , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/patologíaRESUMEN
The aim of this study was to determine the tissue expressions of vascular endothelial growth factor (VEGF) and endocan in adrenal cortical tumors and the factors associated with them. The study included 6 subjects with adrenocortical adenoma (ACA), 7 subjects with adrenocortical carcinoma (ACC), and 13 control subjects with a normal adrenal cortex. The status of VEGF and endocan expression was determined by the proportions of cells staining on a scale ranging from negative (not staining at all) to strongly positive. VEGF expression was detected in 1 (16.7%) of 6 subjects in the ACA group and in 6 (85.7%) of 7 subjects in the ACC group. VEGF expression was not detected in any of the subjects in the control group. Endocan expression was detected in 6 (100%) of 6 subjects in the ACA group and in 7 (100%) of 7 subjects in the ACC group, while it was detected in only 4 (30.7%) of 13 subjects in the control group. VEGF was expressed with a high frequency in subjects with ACC and with a low frequency in subjects with ACA, but it was not expressed in subjects with normal adrenal cortex tissue. Although endocan was expressed with a higher frequency in subjects with ACC and ACA, it was also expressed in subjects with normal adrenal cortex tissue. The percentage of cells expressed endocan in subjects with ACC was also significantly higher than in subjects with both ACA and normal adrenal cortex.
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Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Carcinoma Corticosuprarrenal , Proteínas de Neoplasias , Proteoglicanos , Factor A de Crecimiento Endotelial Vascular , Humanos , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/genética , Masculino , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/biosíntesis , Femenino , Proteoglicanos/metabolismo , Proteoglicanos/genética , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Pronóstico , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Adenoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/metabolismo , Carcinoma Corticosuprarrenal/patología , Anciano , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/patología , Adulto JovenRESUMEN
BACKGROUND: You Only Look Once version 5 (YOLOv5), a one-stage deep-learning (DL) algorithm for object detection and classification, offers high speed and accuracy for identifying targets. PURPOSE: To investigate the feasibility of using the YOLOv5 algorithm to non-invasively distinguish between aldosterone-producing adenomas (APAs) and non-functional adrenocortical adenomas (NF-ACAs) on computed tomography (CT) images. MATERIAL AND METHODS: A total of 235 patients who were diagnosed with ACAs between January 2011 and July 2022 were included in this study. Of the 215 patients, 81 (37.7%) had APAs and 134 (62.3%) had NF-ACAs' they were randomly divided into either the training set or the validation set at a ratio of 9:1. Another 20 patients, including 8 (40.0%) with APA and 12 (60.0%) with NF-ACA, were collected for the testing set. Five submodels (YOLOv5n, YOLOv5s, YOLOv5m, YOLOv5l, and YOLOv5x) of YOLOv5 were trained and evaluated on the datasets. RESULTS: In the testing set, the mAP_0.5 value for YOLOv5x (0.988) was higher than the values for YOLOv5n (0.969), YOLOv5s (0.965), YOLOv5m (0.974), and YOLOv5l (0.983). The mAP_0.5:0.95 value for YOLOv5x (0.711) was also higher than the values for YOLOv5n (0.587), YOLOv5s (0.674), YOLOv5m (0.671), and YOLOv5l (0.698) in the testing set. The inference speed of YOLOv5n was 2.4â ms in the testing set, which was the fastest among the five submodels. CONCLUSION: The YOLOv5 algorithm can accurately and efficiently distinguish between APAs and NF-ACAs on CT images, especially YOLOv5x has the best identification performance.
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Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Aldosterona , Tomografía Computarizada por Rayos X , Humanos , Masculino , Femenino , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/metabolismo , Adenoma Corticosuprarrenal/diagnóstico por imagen , Adenoma Corticosuprarrenal/metabolismo , Persona de Mediana Edad , Aldosterona/metabolismo , Tomografía Computarizada por Rayos X/métodos , Adulto , Diagnóstico Diferencial , Estudios de Factibilidad , Anciano , Aprendizaje Profundo , Algoritmos , Estudios RetrospectivosRESUMEN
Background: Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies. Objective: We aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC. Methods: In vitro mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing. Results: PDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs. Conclusion: ACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Antineoplásicos Hormonales , Mitotano , Pruebas de Farmacogenómica , Humanos , Mitotano/uso terapéutico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Femenino , Masculino , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/farmacología , Persona de Mediana Edad , Adulto , Anciano , FarmacogenéticaRESUMEN
Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remains incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside snRNA-seq data sets from normal adrenal glands (NAGs). We find the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically "cold" tumour. Our analysis identifies three separate groups of ACC samples that are characterised by different relative compositions of adrenocortical cell types. These include cell populations that are specifically enriched in the most clinically aggressive and hormonally active tumours, displaying hallmarks of reorganised cell mechanobiology and dysregulated steroidogenesis, respectively. We also identified and validated a population of mitotically active adrenocortical cells that strongly overexpress genes POLQ, DIAPH3 and EZH2 to support tumour expansion alongside an LGR4+ progenitor-like or cell-of-origin candidate for adrenocortical carcinogenesis. Trajectory inference suggests the fate adopted by malignant adrenocortical cells upon differentiation is associated with the copy number or allelic balance state of the imprinted DLK1/MEG3 genomic locus, which we verified by assessing bulk tumour DNA methylation status. In conclusion, our results therefore provide new insights into the clinical and cellular heterogeneity of ACC, revealing how genetic perturbations to healthy adrenocortical renewal and zonation provide a molecular basis for disease pathogenesis.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Humanos , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Microambiente Tumoral/genética , Análisis de la Célula Individual , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Unión al Calcio , Proteínas de la MembranaRESUMEN
INTRODUCTION: The fluctuations of the intracellular Ca2+ concentration ([Ca2+]i) are key physiological signals for cell function under normal conditions and can undergo profound alterations in disease states, as high blood pressure due to endocrine disorders like primary aldosteronism (PA). However, when assessing such fluctuations several parameters in the Ca2+ signal dynamics need to be considered, which renders their assessment challenging. AIM: Aim to develop an observer-independent custom-made pipeline to analyze Ca2+ dynamics in terms of frequency and peak parameters, as amplitude, full width at half maximum (FWHM) and area under the curve (AUC). METHODS: We applied a custom-made methodology to aldosterone-producing adenoma (APA) and APA adjacent cells (AAC) and found this pipeline to be suitable for monitoring and processing a wide-range of [Ca2+]i events in these cell types delivering reproducible results. CONCLUSION: The designed pipeline can provide a useful tool for [Ca2+]i signal analysis that allows comparisons of Ca2+ dynamics not only in PA, but in other cell phenotypes that are relevant for the regulation of blood pressure.
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Neoplasias de la Corteza Suprarrenal , Corteza Suprarrenal , Adenoma Corticosuprarrenal , Señalización del Calcio , Hiperaldosteronismo , Humanos , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Hiperaldosteronismo/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , Calcio/metabolismo , Reproducibilidad de los Resultados , Células Cultivadas , Factores de TiempoRESUMEN
BACKGROUND: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood. METHODS: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours. FINDINGS: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response. INTERPRETATION: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues. FUNDING: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.
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Neoplasias de la Corteza Suprarrenal , Hidrocortisona , Humanos , Hidrocortisona/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Mutación , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/patología , Perfilación de la Expresión Génica , Transcriptoma , Esteroides/biosíntesis , Esteroides/metabolismo , Adenoma/patología , Adenoma/metabolismo , Adenoma/genética , Masculino , Femenino , Persona de Mediana EdadRESUMEN
Adrenocortical carcinoma (ACC) is a rare malignancy originating in the adrenal glands, aldosterone-producing ACC, even rarer. Papillary thyroid carcinoma (PTC), by contrast, accounts for the majority of thyroid carcinomas. We herein describe the first reported case of a female with comorbidities of aldosterone-producing ACC, PTC, and Graves' Disease(GD). The patient achieved transient clinical remission following adrenalectomy. However, three months later, aldosterone-producing ACC lung metastases emerged. Subsequently, within another three-month interval, she developed thyroid eye disease(TED). The patient died roughly one year after the adrenal operation. Exome sequencing did not reveal associations between aldosterone-producing ACC, PTC, and GD, and the underlying concurrence mechanism has yet to be elucidated. Further research of similar cases are needed to confirm potential links between the three pathologies.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Aldosterona , Enfermedad de Graves , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Femenino , Cáncer Papilar Tiroideo/metabolismo , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/genética , Carcinoma Corticosuprarrenal/metabolismo , Carcinoma Corticosuprarrenal/patología , Enfermedad de Graves/metabolismo , Enfermedad de Graves/complicaciones , Enfermedad de Graves/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/complicaciones , Aldosterona/metabolismo , Persona de Mediana Edad , Adrenalectomía , Resultado FatalRESUMEN
The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.
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Adrenalectomía , Comorbilidad , Hidrocortisona , Humanos , Hidrocortisona/metabolismo , Hidrocortisona/sangre , Síndrome de Cushing/terapia , Síndrome de Cushing/epidemiología , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/fisiopatología , Síndrome de Cushing/metabolismo , Adenoma Corticosuprarrenal/terapia , Adenoma Corticosuprarrenal/diagnóstico , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/epidemiología , Adenoma Corticosuprarrenal/complicaciones , Neoplasias de las Glándulas Suprarrenales/terapia , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/fisiopatología , Neoplasias de la Corteza Suprarrenal/terapia , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/epidemiología , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/fisiopatologíaRESUMEN
Objectives: Adrenal tumors are common, but adrenocortical carcinomas (ACCs) are a rare and challenging form of cancer to diagnose and manage.This study aimed to explore the critical role of mitochondrial quality in maintaining cellular function and the implications of the abnormal expression of mitochondrial metabolism-related proteins observed in ACC patients. We focused on identifying the connection between mitochondrial quality and the development of ACC at molecular and genomic levels. Methods: We compared mitochondrial quality-related genes (MQRGs) across ACC subtypes using overall survival (OS) and disease-free survival (DFS) as evaluation indicators. Furthermore, a novel MQRG score was developed to predict clinical prognosis and guide immunotherapy responses accurately. Results: The majority of MQRGs were upregulated in the ACC samples, correlating to poor prognosis. The MQRG score was confirmed as an independent prognostic factor for ACC, with the high-risk MQRG score group showing a significantly shorter overall survival period. Conclusions: Multilayer alterations in MQRGs are associated with patient prognosis and immune cell infiltration characteristics. This comprehensive analysis of MQRGs can contribute to a deeper understanding of potential differences in ACC patients' tumor microenvironment. This can influence clinical decision-making and advanced prognosis prediction, thereby offering new insights into personalized treatments in ACC.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Humanos , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/metabolismo , Pronóstico , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Supervivencia sin Enfermedad , Microambiente Tumoral/genéticaRESUMEN
CONTEXT: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous. OBJECTIVE: Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. METHODS: The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. RESULTS: PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P = .04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells. CONCLUSION: The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Antígeno B7-H1 , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Humanos , Antígeno CTLA-4/metabolismo , Masculino , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/mortalidad , Carcinoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/mortalidad , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/inmunología , Femenino , Receptor de Muerte Celular Programada 1/metabolismo , Persona de Mediana Edad , Pronóstico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/análisis , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Adulto Joven , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Adolescente , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). Although it has been used for many years, its mechanism of action remains elusive. H295R cells are, in ACC, an essential tool to evaluate drug mechanisms, although they often lead to conflicting results. METHODS: Using different in vitro biomolecular technologies and biochemical/biophysical experiments, we evaluated how the presence of "confounding factors" in culture media and patient sera could reduce the pharmacological effect of mitotane and its metabolites. RESULTS: We discovered that albumin, the most abundant protein in the blood, was able to bind mitotane. This interaction altered the effect of the drug by blocking its biological activity. This blocking effect was independent of the albumin source or methodology used and altered the assessment of drug sensitivity of the cell lines. CONCLUSIONS: In conclusion, we have for the first time demonstrated that albumin does not only act as an inert drug carrier when mitotane or its metabolites are present. Indeed, our experiments clearly indicated that both albumin and human serum were able to suppress the pharmacological effect of mitotane in vitro. These experiments could represent a first step towards the individualization of mitotane treatment in this rare tumor.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Humanos , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/patología , Albúminas , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Mitotano/farmacología , Mitotano/uso terapéutico , Mitotano/metabolismoRESUMEN
Mitotane is a chiral drug used to treat adrenocortical carcinoma, being metabolized to the o,p'-dichlorodiphenyl acetic acid (o,p'-DDA), also a chiral compound. Despite of its therapeutic significance, the overall ratios and enantiomers have not been known. In this study, we analyzed the enantiomers of mitotane and o,p'-DDA in the plasma of patients by a newly developed chiral-phase method employed in two-dimensional chromatography. Important differences were observed in the ratio of (S)/(R)-mitotane, which varied substantially from 1:1.2 to 1:10 whereas the (S)/(R)-o,p'-DDA ratio was relatively conserved, at approximately 2:1. These findings provide evidence for the enantioselective metabolism and provide a method for further analyses of mitotane and metabolites, which can explain the variation in the therapeutic response.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Humanos , Mitotano/uso terapéutico , Mitotano/metabolismo , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Estereoisomerismo , Cromatografía Líquida de Alta Presión/métodos , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/metabolismoRESUMEN
Adrenocortical carcinoma (ACC) is a rare but malignant tumor. Surgical removal, radiotherapy and combined chemotherapy are commonly used to treat ACC. Despite efforts for several decades, the mortality rate of ACC remains high after treatments. Therefore, identifying a novel therapeutic molecule is important to increase the survival rate of patients with ACC. The centrosome is a microtubule organizing center, and it also functions as a signaling hub to coordinate cell cycle progression. Deficiencies in the regulation of centrosome copy numbers may cause cell cycle arrest or even apoptosis. BI2536 is a polo like kinase 1selective inhibitor and has been tested for the treatment of several types of cancer, including lung, oral and gastric cancer. However, to the best of our knowledge, its effects on ACC have not yet been examined. The present study revealed that BI2536 inhibited Y1 ACC cell proliferation in a time and dosedependent manner. BI2536 blocked cell cycle progression and also induced cell apoptosis as shown by flow cytometry. Furthermore, following BI2536 treatment, centrosome amplification was induced, which resulted in aberrant mitosis. In terms of the mechanism, BI2536 induced DNA damage as evidenced by γH2AX staining and comet assay, followed by activation of ATM serine/threonine kinaseERK signaling to promote centrosome amplification. Therefore, the present study suggested that BI2536 could be used as an adjuvant therapy in the treatment of ACC, and also revealed the underlying molecular mechanism.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Humanos , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Línea Celular Tumoral , Proteínas de Ciclo Celular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Centrosoma/metabolismo , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Quinasa Tipo Polo 1RESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.