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3 pages, 187 KiB

Open AccessEditorial

New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas

by Peter Igaz

Cancers 2022, 14(4), 1094; https://doi.org/10.3390/cancers14041094 - 21 Feb 2022

Viewed by 1517

Abstract

This article collection includes 16 scientific papers that present the current state of the art of genetics and genomics research in the fascinating field of adrenal tumors [...] Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

Research

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14 pages, 1327 KiB

Open AccessArticle

Tissue miRNA Combinations for the Differential Diagnosis of Adrenocortical Carcinoma and Adenoma Established by Artificial Intelligence

by Péter István Turai, Zoltán Herold, Gábor Nyirő, Katalin Borka, Tamás Micsik, Judit Tőke, Nikolette Szücs, Miklós Tóth, Attila Patócs and Peter Igaz

Cancers 2022, 14(4), 895; https://doi.org/10.3390/cancers14040895 - 11 Feb 2022

Cited by 12 | Viewed by 2628

Abstract

The histological analysis of adrenal tumors is difficult and requires great expertise. Tissue microRNA (miRNA) expression is distinct between benign and malignant tumors of several organs and can be useful for diagnostic purposes. MiRNAs are stable and their expression can be reliably reproduced [...] Read more.

The histological analysis of adrenal tumors is difficult and requires great expertise. Tissue microRNA (miRNA) expression is distinct between benign and malignant tumors of several organs and can be useful for diagnostic purposes. MiRNAs are stable and their expression can be reliably reproduced from archived formalin-fixed, paraffin-embedded (FFPE) tissue blocks. Our purpose was to assess the potential applicability of combinations of literature-based miRNAs as markers of adrenocortical malignancy. Archived FFPE tissue samples from 10 adrenocortical carcinoma (ACC), 10 adrenocortical adenoma (ACA) and 10 normal adrenal cortex samples were analyzed in a discovery cohort, while 21 ACC and 22 ACA patients were studied in a blind manner in the validation cohort. The expression of miRNA was determined by RT-qPCR. Machine learning and neural network-based methods were used to find the best performing miRNA combination models. To evaluate diagnostic applicability, ROC-analysis was performed. We have identified three miRNA combinations (hsa-miR-195 + hsa-miR-210 + hsa-miR-503; hsa-miR-210 + hsa-miR-375 + hsa-miR-503 and hsa-miR-210 + hsa-miR-483-5p + hsa-miR-503) as unexpectedly good predictors to determine adrenocortical malignancy with sensitivity and specificity both of over 90%. These miRNA panels can supplement the histological examination of removed tumors and could even be performed from small volume adrenal biopsy samples preoperatively. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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15 pages, 1435 KiB

Open AccessArticle

Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors: Lessons Learned and Way Forward

by Karina C. F. Tosin, Edith F. Legal, Mara A. D. Pianovski, Humberto C. Ibañez, Gislaine Custódio, Denise S. Carvalho, Mirna M. O. Figueiredo, Anselmo Hoffmann Filho, Carmem M. C. M. Fiori, Ana Luiza M. Rodrigues, Rosiane G. Mello, Karin R. P. Ogradowski, Ivy Z. S. Parise, Tatiana E. J. Costa, Viviane S. Melanda, Flora M. Watanabe, Denise B. Silva, Heloisa Komechen, Henrique A. Laureano, Edna K. Carboni, Ana P. Kuczynski, Gabriela C. F. Luiz, Leniza Lima, Tiago Tormen, Viviane K. Q. Gerber, Tania H. Anegawa, Sylvio G. A. Avilla, Renata B. Tenório, Elaine L. Mendes, Rayssa D. Fachin Donin, Josiane Souza, Vanessa N. Kozak, Gisele S. Oliveira, Deivid C. Souza, Israel Gomy, Vinicius B. Teixeira, Helena H. L. Borba, Nilton Kiesel Filho, Guilherme A. Parise, Raul C. Ribeiro and Bonald C. Figueiredo Show full author list Hide full author list

Cancers 2021, 13(23), 6111; https://doi.org/10.3390/cancers13236111 - 3 Dec 2021

Cited by 5 | Viewed by 3331

Abstract

The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not [...] Read more.

The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012–2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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16 pages, 598 KiB

Open AccessArticle

A Multicenter Epidemiological Study on Second Malignancy in Non-Syndromic Pheochromocytoma/Paraganglioma Patients in Italy

by Letizia Canu, Soraya Puglisi, Paola Berchialla, Giuseppina De Filpo, Francesca Brignardello, Francesca Schiavi, Alfonso Massimiliano Ferrara, Stefania Zovato, Michaela Luconi, Anna Pia, Marialuisa Appetecchia, Emanuela Arvat, Claudio Letizia, Mauro Maccario, Mirko Parasiliti-Caprino, Barbara Altieri, Antongiulio Faggiano, Roberta Modica, Valentina Morelli, Maura Arosio, Uberta Verga, Micaela Pellegrino, Luigi Petramala, Antonio Concistrè, Paola Razzore, Tonino Ercolino, Elena Rapizzi, Mario Maggi, Antonio Stigliano, Jacopo Burrello, Massimo Terzolo, Giuseppe Opocher, Massimo Mannelli and Giuseppe Reimondo Show full author list Hide full author list

Cancers 2021, 13(22), 5831; https://doi.org/10.3390/cancers13225831 - 20 Nov 2021

Cited by 5 | Viewed by 2374

Abstract

No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in [...] Read more.

No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. <50-year category; HR 3.46, 95% CI 1.67–7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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12 pages, 1950 KiB

Open AccessArticle

Targeting the Redox Balance Pathway Using Ascorbic Acid in sdhb Zebrafish Mutant Larvae

by Margo Dona, Maaike Lamers, Svenja Rohde, Marnix Gorissen and Henri J. L. M. Timmers

Cancers 2021, 13(20), 5124; https://doi.org/10.3390/cancers13205124 - 13 Oct 2021

Cited by 3 | Viewed by 2094

Abstract

Patients with mutations in the β-subunit of the succinate dehydrogenase (SDHB) have the highest risk to develop incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy development is hindered by limited possibilities to test new therapeutic strategies in vivo. One possible molecular mechanism [...] Read more.

Patients with mutations in the β-subunit of the succinate dehydrogenase (SDHB) have the highest risk to develop incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy development is hindered by limited possibilities to test new therapeutic strategies in vivo. One possible molecular mechanism of SDHB-associated tumorigenesis originates in an overproduction of reactive oxygen species (ROS) due to mitochondrial dysfunction. Ascorbic acid (Vitamin C) has already been shown to act as anti-cancer agent in several clinical trials for various types of cancer. In this study, the potential of the sdhb^rmc200 zebrafish model to study SDHB-associated PPGLs using a drug screening approach was investigated. First, we identified increased basal ROS levels in homozygous sdhb larvae compared to heterozygous and wild-type siblings. Using a semi high-throughput drug screening, the effectiveness of different dosages of anti- and pro-oxidant Vitamin C were assessed to evaluate differences in survival, ROS levels, and locomotor activity. Low-dosage levels of Vitamin C induced a decrease of ROS levels but no significant effects on lifespan. In contrast, high-dosage levels of Vitamin C shortened the lifespan of the homozygous sdhb^rmc200 larvae while not affecting the lifespan of heterozygous and wild-type siblings. These results validated the sdhb^rmc200 zebrafish model as a powerful drug screening tool that may be used to identify novel therapeutic targets for SDHB-associated PPGLs. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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22 pages, 2373 KiB

Open AccessArticle

Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma

by María Monteagudo, Paula Martínez, Luis J. Leandro-García, Ángel M. Martínez-Montes, Bruna Calsina, Marta Pulgarín-Alfaro, Alberto Díaz-Talavera, Sara Mellid, Rocío Letón, Eduardo Gil, Manuel Pérez-Martínez, Diego Megías, Raúl Torres-Ruiz, Sandra Rodriguez-Perales, Patricia González, Eduardo Caleiras, Scherezade Jiménez-Villa, Giovanna Roncador, Cristina Álvarez-Escolá, Rita M. Regojo, María Calatayud, Sonsoles Guadalix, Maria Currás-Freixes, Elena Rapizzi, Letizia Canu, Svenja Nölting, Hanna Remde, Martin Fassnacht, Nicole Bechmann, Graeme Eisenhofer, Massimo Mannelli, Felix Beuschlein, Marcus Quinkler, Cristina Rodríguez-Antona, Alberto Cascón, María A. Blasco, Cristina Montero-Conde and Mercedes Robledo Show full author list Hide full author list

Cancers 2021, 13(19), 4758; https://doi.org/10.3390/cancers13194758 - 23 Sep 2021

Cited by 17 | Viewed by 4323

Abstract

One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation [...] Read more.

One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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11 pages, 2000 KiB

Open AccessArticle

Characteristics of a Novel ATP2B3 K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma

by Hung-Wei Liao, Kang-Yung Peng, Vin-Cent Wu, Yen-Hung Lin, Shuei-Liong Lin, Wei-Chou Lin, Jeff S. Chueh and on behalf of (TAIPAI) Study Group

Cancers 2021, 13(18), 4729; https://doi.org/10.3390/cancers13184729 - 21 Sep 2021

Cited by 1 | Viewed by 2546

Abstract

In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic [...] Read more.

In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic ATP2B3 K416_F418delinsN mutation. The affected individual was a 53 year-old man with a 4 year history of hypertension. Computed tomography (CT) showed bilateral adrenal masses of 1.6 (left) and 0.5 cm (right) in size. An adrenal venous sampling (AVS) showed a lateralization index (LI) of 2.2 and a contralateral suppression index (CLS) of 0.12; indicating left functional predominance. After a left unilateral adrenalectomy, he achieved partial biochemical and hypertension–remission. This classical adenoma harbored a novel ATP2B3 K416_F418delinsN somatic mutation, which is a deletion from nucleotides 1248 to 1253. The translated amino acid sequence from 416 to 418, reading as lysine-phenylalanine-phenylalanine, was deleted; however, an asparagine was inserted due to merging of residual nucleotide sequences. The CYP11B2 immunohistochemistry staining demonstrated strong immunoreactivity in this classical adenoma. The ATP2B3 K416_F418delinsN mutation is a functional mutation in APA, since HAC15 cells, a human adrenal cell line, transfected with the mutant gene showed increased CYP11B2 expression and aldosterone production. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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13 pages, 3652 KiB

Open AccessArticle

Identifying New Potential Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning

by André Marquardt, Laura-Sophie Landwehr, Cristina L. Ronchi, Guido di Dalmazi, Anna Riester, Philip Kollmannsberger, Barbara Altieri, Martin Fassnacht and Silviu Sbiera

Cancers 2021, 13(18), 4671; https://doi.org/10.3390/cancers13184671 - 17 Sep 2021

Cited by 13 | Viewed by 3287

Abstract

Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset [...] Read more.

Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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13 pages, 723 KiB

Open AccessArticle

KCNJ5 Somatic Mutations in Aldosterone-Producing Adenoma Are Associated with a Greater Recovery of Arterial Stiffness

by Yi-Yao Chang, Chien-Ting Pan, Zheng-Wei Chen, Cheng-Hsuan Tsai, Shih-Yuan Peng, Chin-Chen Chang, Bo-Ching Lee, Che-Wei Liao, Kang-Yung Peng, Yu-Wei Chiu, Chia-Hung Chou, Vin-Cent Wu, Li-Yu Daisy Liu, Chi-Sheng Hung and Yen-Hung Lin

Cancers 2021, 13(17), 4313; https://doi.org/10.3390/cancers13174313 - 26 Aug 2021

Cited by 6 | Viewed by 2729

Abstract

Primary aldosteronism is the most common form of secondary hypertension and induces various cardiovascular injuries. In aldosterone-producing adenoma (APA), the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of confounding factors is uncertain. We enrolled 213 APA patients who were [...] Read more.

Primary aldosteronism is the most common form of secondary hypertension and induces various cardiovascular injuries. In aldosterone-producing adenoma (APA), the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of confounding factors is uncertain. We enrolled 213 APA patients who were scheduled to undergo adrenalectomy. KCNJ5 gene sequencing of APA was performed. After propensity score matching (PSM) for age, sex, body mass index, blood pressure, number of hypertensive medications, and hypertension duration, there were 66 patients in each group with and without KCNJ5 mutations. The mutation carriers had a higher aldosterone level and lower log transformed brachial–ankle pulse wave velocity (baPWV) than the non-carriers before PSM, but no difference in log baPWV after PSM. One year after adrenalectomy, the mutation carriers had greater decreases in log plasma aldosterone concentration, log aldosterone–renin activity ratio, and log baPWV than the non-carriers after PSM. Only the mutation carriers had a significant decrease in log baPWV after surgery both before and after PSM. KCNJ5 mutations were not correlated with baseline baPWV after PSM but were significantly correlated with ∆baPWV after surgery both before and after PSM. Conclusively, APA patients with KCNJ5 mutations had a greater regression in arterial stiffness after adrenalectomy than those without mutations. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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22 pages, 1551 KiB

Open AccessArticle

Analytical Performance of NGS-Based Molecular Genetic Tests Used in the Diagnostic Workflow of Pheochromocytoma/Paraganglioma

by Balazs Sarkadi, Istvan Liko, Gabor Nyiro, Peter Igaz, Henriett Butz and Attila Patocs

Cancers 2021, 13(16), 4219; https://doi.org/10.3390/cancers13164219 - 22 Aug 2021

Cited by 4 | Viewed by 2965

Abstract

Next Generation Sequencing (NGS)-based methods are high-throughput and cost-effective molecular genetic diagnostic tools. Targeted gene panel and whole exome sequencing (WES) are applied in clinical practice for assessing mutations of pheochromocytoma/paraganglioma (PPGL) associated genes, but the best strategy is debated. Germline mutations of [...] Read more.

Next Generation Sequencing (NGS)-based methods are high-throughput and cost-effective molecular genetic diagnostic tools. Targeted gene panel and whole exome sequencing (WES) are applied in clinical practice for assessing mutations of pheochromocytoma/paraganglioma (PPGL) associated genes, but the best strategy is debated. Germline mutations of at the least 18 PPGL genes are present in approximately 20–40% of patients, thus molecular genetic testing is recommended in all cases. We aimed to evaluate the analytical and clinical performances of NGS methods for mutation detection of PPGL-associated genes. WES (three different library preparation and bioinformatics workflows) and an in-house, hybridization based gene panel (endocrine-onco-gene-panel- ENDOGENE) was evaluated on 37 (20 WES and 17 ENDOGENE) samples with known variants. After optimization of the bioinformatic workflow, 61 additional samples were tested prospectively. All clinically relevant variants were validated with Sanger sequencing. Target capture of PPGL genes differed markedly between WES platforms and genes tested. All known variants were correctly identified by all methods, but methods of library preparations, sequencing platforms and bioinformatical settings significantly affected the diagnostic accuracy. The ENDOGENE panel identified several pathogenic mutations and unusual genotype–phenotype associations suggesting that the whole panel should be used for identification of genetic susceptibility of PPGL. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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19 pages, 5315 KiB

Open AccessArticle

Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas

by Siyuan Gong, Martina Tetti, Martin Reincke and Tracy Ann Williams

Cancers 2021, 13(15), 3716; https://doi.org/10.3390/cancers13153716 - 23 Jul 2021

Cited by 7 | Viewed by 3490

Abstract

Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is [...] Read more.

Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is limited. Here, we investigated adrenocortical cell-intrinsic metabolism and the tumor immune microenvironment of APAs and their potential roles in mediating aldosterone production and growth of adrenocortical cells. Using multiple advanced bioinformatics methods, we analyzed gene expression datasets to generate distinct metabolic and immune cell profiles of APAs versus paired adjacent cortex. APAs displayed activation of lipid metabolism, especially fatty acid β-oxidation regulated by PPARα, and glycolysis. We identified an immunosuppressive microenvironment in APAs, with reduced infiltration of CD45⁺ immune cells compared with adjacent cortex, validated by CD45 immunohistochemistry (3.45-fold, p < 0.001). APAs also displayed an association of lipid metabolism with ferroptosis and upregulation of antioxidant systems. In conclusion, APAs exhibit metabolic reprogramming towards fatty acid β-oxidation and glycolysis. Increased lipid metabolism via PPARα may serve as a key mechanism to modulate lipid peroxidation, a hallmark of regulated cell death by ferroptosis. These findings highlight survival advantages for APA tumor cells with metabolic reprogramming properties. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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Review

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15 pages, 1097 KiB

Open AccessReview

New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications

by Sakshi Jhawar, Yasuhiro Arakawa, Suresh Kumar, Diana Varghese, Yoo Sun Kim, Nitin Roper, Fathi Elloumi, Yves Pommier, Karel Pacak and Jaydira Del Rivero

Cancers 2022, 14(3), 594; https://doi.org/10.3390/cancers14030594 - 25 Jan 2022

Cited by 43 | Viewed by 5566

Abstract

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with [...] Read more.

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30–40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2 and HIF2/EPAS; the kinase group or cluster II includes RET, NF1, TMEM127, MAX and HRAS; and the Wnt signaling group or cluster III includes CSDE1 and MAML3. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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15 pages, 504 KiB

Open AccessReview

Circulating microRNAs as Diagnostic Markers in Primary Aldosteronism

by Scott M. MacKenzie, Hannah Saunders, Josie C. van Kralingen, Stacy Robertson, Alexandra Riddell, Maria-Christina Zennaro and Eleanor Davies

Cancers 2021, 13(21), 5312; https://doi.org/10.3390/cancers13215312 - 22 Oct 2021

Cited by 5 | Viewed by 2342

Abstract

Primary aldosteronism (PA) is a common and highly treatable condition, usually resulting from adrenocortical tumorous growth or hyperplasia. PA is currently underdiagnosed owing to its complex and protracted diagnostic procedures. A simplified biomarker-based test would be highly valuable in reducing cardiovascular morbidity and [...] Read more.

Primary aldosteronism (PA) is a common and highly treatable condition, usually resulting from adrenocortical tumorous growth or hyperplasia. PA is currently underdiagnosed owing to its complex and protracted diagnostic procedures. A simplified biomarker-based test would be highly valuable in reducing cardiovascular morbidity and mortality. Circulating microRNAs are emerging as potential biomarkers for a number of conditions due to their stability and accessibility. PA is known to alter microRNA expression in adrenocortical tissue; if these changes or their effects are mirrored in the circulating miRNA profile, then this could be exploited by a diagnostic test. However, the reproducibility of studies to identify biomarker-circulating microRNAs has proved difficult for other conditions due to a series of technical challenges. Therefore, any studies seeking to definitively identify circulating microRNA biomarkers of PA must address this in their design. To this end, we are currently conducting the circulating microRNA arm of the ongoing ENS@T-HT study. In this review article, we present evidence to support the utility of circulating microRNAs as PA biomarkers, describe the practical challenges to this approach and, using ENS@T-HT as an example, discuss how these might be overcome. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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12 pages, 1222 KiB

Open AccessReview

Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies

by Marco Lo Iacono, Soraya Puglisi, Paola Perotti, Laura Saba, Jessica Petiti, Claudia Giachino, Giuseppe Reimondo and Massimo Terzolo

Cancers 2021, 13(21), 5255; https://doi.org/10.3390/cancers13215255 - 20 Oct 2021

Cited by 16 | Viewed by 3205

Abstract

Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and is increasingly used for postoperative adjuvant therapy. Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. [...] Read more.

Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and is increasingly used for postoperative adjuvant therapy. Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. Although it is known that mitotane destroys the adrenal cortex and impairs steroidogenesis, its exact mechanism of action is still unclear. The most used cell models are H295-derived cell strains and SW13 cell lines. The diverging results obtained in presumably identical cell lines highlight the need for a stable in vitro model and/or a standard methodology to perform experiments on H295 strains. The presence of several enzymatic targets responsive to mitotane in mitochondria and mitochondria-associated membranes causes progressive alteration in mitochondrial structure when cells were exposed to mitotane. Confounding factors of culture affecting in vitro experiments could reduce the significance of any molecular mechanism identified in vitro. To ensure experimental reproducibility, particular care should be taken in the choice of culture conditions: aspects such as cell strains, culture serum, lipoproteins concentration, and culture passages should be carefully considered and explicated in the presentation of results. We aimed to review in vitro studies on mitotane effects, highlighting how different experimental conditions might contribute to the controversial findings. If the concerns pointed out in this review will be overcome, the new insights into mitotane mechanism of action observed in-vitro could allow the identification of novel pharmacological molecular pathways to be used to implement personalized therapy. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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14 pages, 1322 KiB

Open AccessReview

Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

by Shahida K. Flores, Cynthia M. Estrada-Zuniga, Keerthi Thallapureddy, Gustavo Armaiz-Peña and Patricia L. M. Dahia

Cancers 2021, 13(18), 4602; https://doi.org/10.3390/cancers13184602 - 14 Sep 2021

Cited by 14 | Viewed by 2800

Abstract

Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in [...] Read more.

Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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Open AccessReview

MicroRNAs, Long Non-Coding RNAs, and Circular RNAs: Potential Biomarkers and Therapeutic Targets in Pheochromocytoma/Paraganglioma

by Peter Istvan Turai, Gábor Nyírő, Henriett Butz, Attila Patócs and Peter Igaz

Cancers 2021, 13(7), 1522; https://doi.org/10.3390/cancers13071522 - 26 Mar 2021

Cited by 18 | Viewed by 2788

Abstract

Around 40% of pheochromocytomas/paragangliomas (PPGL) harbor germline mutations, representing the highest heritability among human tumors. All PPGL have metastatic potential, but metastatic PPGL is overall rare. There is no available molecular marker for the metastatic potential of these tumors, and the diagnosis of [...] Read more.

Around 40% of pheochromocytomas/paragangliomas (PPGL) harbor germline mutations, representing the highest heritability among human tumors. All PPGL have metastatic potential, but metastatic PPGL is overall rare. There is no available molecular marker for the metastatic potential of these tumors, and the diagnosis of metastatic PPGL can only be established if metastases are found at “extra-chromaffin” sites. In the era of precision medicine with individually targeted therapies and advanced care of patients, the treatment options for metastatic pheochromocytoma/paraganglioma are still limited. With this review we would like to nurture the idea of the quest for non-coding ribonucleic acids as an area to be further investigated in tumor biology. Non-coding RNA molecules encompassing microRNAs, long non-coding RNAs, and circular RNAs have been implicated in the pathogenesis of various tumors, and were also proposed as valuable diagnostic, prognostic factors, and even potential treatment targets. Given the fact that the pathogenesis of tumors including pheochromocytomas/paragangliomas is linked to epigenetic dysregulation, it is reasonable to conduct studies related to their epigenetic expression profiles and in this brief review we present a synopsis of currently available findings on the relevance of these molecules in these tumors highlighting their diagnostic potential. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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19 pages, 7655 KiB

Open AccessSystematic Review

Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

by Ariadni Spyroglou, George P. Piaditis, Gregory Kaltsas and Krystallenia I. Alexandraki

Cancers 2021, 13(21), 5582; https://doi.org/10.3390/cancers13215582 - 8 Nov 2021

Cited by 7 | Viewed by 3274

Abstract

Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in [...] Read more.

Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone-producing adenomas (APAs). Methods: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro-RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. Results: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G-coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. Conclusions: These findings can substantially contribute to the development of personalized treatment in patients with PA. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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