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Guoliang Wang Department of Tumor and Immunology, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing, China

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Na Ren Department of Clinical Laboratory Center, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Shengcai Wang Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Xuexi Zhang Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Yanzhen Li Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Nian Sun Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Qiaoyin Liu Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Jie Zhang Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Wenqi Song Department of Clinical Laboratory Center, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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Xin Ni Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, Beijing, China

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It is uncertain whether serum TSH concentration is an independent risk factor for the malignancy of pediatric thyroid nodules. We sought the association of serum TSH concentration with the malignancy of pediatric thyroid nodules and with the characteristics of pediatric thyroid cancer. A total of 219 pediatric thyroid nodule patients were collected retrospectively for 5 consecutive years. The medical records collected included sex, age, serum TSH concentration, thyroid autoantibody status, thyroid ultra-sonography parameters, histological type, and pathological TNM stages. The serum TSH concentrations were compared between benign and malignant nodules or corresponding subgroups. Binary logistic regression analysis was used to evaluate the correlation of TSH concentration with the malignancy of thyroid nodules and with the characteristics of pediatric thyroid cancer. There was no significant difference in TSH concentration between benign nodule and thyroid cancer in total subjects and various subgroups. The serum TSH level was not correlated with the malignancy of thyroid nodules in univariate analysis, but negatively correlated with the malignancy of thyroid nodules (odds ratio = 0.856, P  = 0.013) after adjusting for the patients’ sex, age, thyroid autoantibody status, and nodule size. The serum TSH level was not correlated with the tumor characteristics in pediatric thyroid cancer patients. In conclusion, the serum TSH concentration seems not to be a carcinogenic factor in pediatric thyroid nodule patients, nor to be an independent risk factor for characteristics of pre-existing pediatric thyroid cancers.

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Johan O Paulsson Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital CCK, Stockholm, Sweden

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Ninni Mu Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital CCK, Stockholm, Sweden

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Ivan Shabo Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Na Wang Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital CCK, Stockholm, Sweden

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Jan Zedenius Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Catharina Larsson Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital CCK, Stockholm, Sweden

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C Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital CCK, Stockholm, Sweden

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Telomerase reverse transcriptase (TERT) promoter mutations have been linked to adverse clinical parameters in thyroid cancer, but TERT-expressing tumours are not always mutated. Little is known regarding other TERT-related genetic aberrations. To delineate the role of TERT gene aberrancies in follicular thyroid tumours, 95 follicular carcinomas (FTCs), 43 follicular adenomas (FTAs) and 33 follicular tumours of uncertain malignant potential (FT-UMPs) were collected. The tumours were assayed for TERT expression, TERT promoter mutations, TERT promoter hypermethylation and TERT gene copy number (CN) alterations and the results were compared to clinical parameters. Cases with mutation, detectable mRNA expression, CN gain or hypermethylation were classified as TERT aberrant, and these aberrancies were regularly found in FTC and FT-UMP but uncommonly found in FTA. In total, 59% FTCs and 63% FT-UMPs exhibited one or more of these TERT gene aberrancies. Moreover, 24 out of 28 FTCs (86%) with TERT expression displayed an evident TERT gene aberration, and statistics showed an increased risk for relapse in FTCs with TERT expression, CN gain or hypermethylation. We conclude that TERT expression in follicular thyroid tumours is coupled to promoter mutations, CN gain and increased promoter methylation. The molecular similarities regarding TERT aberrations between the FTC and FT-UMP groups indicate that a significant subset of FT-UMP cases may display future recurrences. TERT aberrancies are thus promising as future additional markers for determining malignant potential of follicular thyroid tumours.

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Tiantian Liu
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Taylor C Brown Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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C Christofer Juhlin Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Adam Andreasson Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Na Wang Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Martin Bäckdahl Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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James M Healy Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Manju L Prasad Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Reju Korah Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Tobias Carling Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden
Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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Dawei Xu
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Catharina Larsson Department of Medicine-Solna, Yale Endocrine Neoplasia Laboratory, Department of Surgery, Departments of Oncology-Pathology, Molecular Medicine and Surgery, Department of Pathology, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76 Stockholm, Sweden

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The telomerase reverse transcriptase gene (TERT) encodes the reverse transcriptase component of the telomerase complex, which is essential for telomere stabilization and cell immortalization. Recent studies have demonstrated a transcriptional activation role for the TERT promoter mutations C228T and C250T in many human cancers, as well as a role in aggressive disease with potential clinical applications. Although telomerase activation is known in adrenal tumors, the underlying mechanisms are not established. We assessed C228T and C250T TERT mutations by direct Sanger sequencing in tumors of the adrenal gland, and further evaluated potential associations with clinical parameters and telomerase activation. A total of 199 tumors were evaluated, including 34 adrenocortical carcinomas (ACC), 47 adrenocortical adenomas (ACA), 105 pheochromocytomas (PCC; ten malignant and 95 benign), and 13 abdominal paragangliomas (PGL; nine malignant and four benign). TERT expression levels were determined by quantitative RT-PCR. The C228T mutation was detected in 4/34 ACCs (12%), but not in any ACA (P=0.028). C228T was also observed in one benign PCC and in one metastatic PGL. The C250T mutation was not observed in any case. In the ACC and PGL groups, TERT mutation-positive cases exhibited TERT expression, indicating telomerase activation; however, since expression was also revealed in TERT WT cases, this could denote additional mechanisms of TERT activation. To conclude, the TERT promoter mutation C228T is a recurrent event associated with TERT expression in ACCs, but rarely occurs in PGL and PCC. The involvement of the TERT gene in ACC represents a novel mutated gene in this entity.

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Johan O Paulsson Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Na Wang Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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Jiwei Gao Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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Adam Stenman Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Jan Zedenius Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Ninni Mu Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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Weng-Onn Lui Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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Catharina Larsson Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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C Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden

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Mutations in the miRNA enzyme gene DICER1 have been reported in several endocrine malignancies and is associated with the rare tumour-predisposing DICER1 syndrome. DICER1 mutations have been reported in subsets of follicular thyroid carcinoma (FTC), but the role of DICER1 in follicular thyroid tumorigenesis has not been extensively studied. In this study, we investigate the role of DICER1 in 168 follicular thyroid tumours and in an FTC cell line. We found rare DICER1 mutations in paediatric FTC cases and a general DICER1 down-regulation in FTCs visualized both on mRNA and protein level, especially pronounced in Hürthle cell carcinoma (HuCC). The down-regulation was also evident in follicular thyroid adenomas (FTAs), suggesting a potential early step in tumorigenesis. The expression of DICER1 was lower in FTCs of older patients in which TERT promoter mutations are more frequent. In FTCs, DICER1 down-regulation was not caused by gene copy number loss but significantly correlated to expression of the transcription factor GABPA in clinical cases. GABPA was found to bind to the DICER1 promoter and regulate DICER1 expression in vitro, as GABPA depletion in FTC cell lines reduced DICER1 expression. This in turn stimulated cell proliferation and affected the miRNA machinery, evident by altered miRNA expression. To conclude, we show that GABPA directly regulates DICER1 in FTC, acting as a tumour suppressor and displaying down-regulation in clinical samples. We also show reduced expression of DICER1 in benign and malignant follicular thyroid tumours, suggesting a potentially early tumorigenic role of this gene aberrancy.

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Hongqiang Wang Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Department of Oncology, Zhoushan Hospital, Zhoushan, China

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Rui Zhou Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Li Sun Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Jianling Xia Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Xuchun Yang Department of Oncology, Zhoushan Hospital, Zhoushan, China

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Changqie Pan Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Na Huang Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Min Shi Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Jianping Bin Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Yulin Liao Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Wangjun Liao Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo. Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.

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Fredrika Svahn Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Karolina Solhusløkk Höse Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Adam Stenman Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Yaxuan Liu Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China

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Jan Calissendorff Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Emma Tham Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

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Ákos Végvári Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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Roman A Zubarev Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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Na Wang Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden

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Reju Korah Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA

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Tobias Carling Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
Carling Adrenal Center, Tampa, Florida, USA

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Jan Zedenius Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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Robert Bränström Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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C Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital Stockholm, Sweden

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Catharina Larsson Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here, we re-analyzed whole-exome sequencing data for PCC patients and identified two patients with rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and from analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in six PCC cases. Three of these were constitutional, and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak or negative staining. Reduced CACNA1H gene expression was especially pronounced in PCC compared to aPGL and in PPGL with cluster 2 kinase signaling phenotype. Furthermore, CACNA1H levels correlated with HIF1A and HIF2A. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles, determined by mass spectrometry, as well as a shift in the membrane potential where maximum calcium currents were observed, as determined by electrophysiology. The findings suggest the involvement of CACNA1H/CaV3.2 in pheochromocytoma development and establish a potential link between the etiology of adrenomedullary and adrenocortical tumor development.

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