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Felix Haglund Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Carl Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Taylor Brown Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Mehran Ghaderi Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Tiantian Liu Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Adam Stenman Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Andrii Dinets Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Manju Prasad Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Reju Korah Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Dawei Xu Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Tobias Carling Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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Catharina Larsson Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Karolinska University Hospital, SE-171 76, Stockholm, Sweden

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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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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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