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

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Ozgur Mete Department of Pathology, University Health Network, Toronto, ON, Canada
Endocrine Oncology Site, Princess Margaret Cancer Centre, Toronto, ON, Canada
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

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Zubair W Baloch Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

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The fifth edition of the Classification of Endocrine and Neuroendocrine Tumors has been released by the World Health Organization. This timely publication integrates several changes to the nomenclature of non-neoplastic and neoplastic thyroid diseases, as well as novel concepts that are essential for patient management. The heterogeneous group of non-neoplastic and benign neoplastic lesions are now collectively termed as ‘thyroid follicular nodular disease’ to better reflect the clonal and non-clonal proliferations that clinically present as multinodular goiter. Thyroid neoplasms originating from follicular cells are distinctly divided into benign, low-risk and malignant neoplasms. The new classification scheme stresses that papillary thyroid carcinoma (PTC) should be subtyped based on histomorphologic features irrespective of tumor size to avoid treating all sub-centimeter/small lesions as low-risk disease. Formerly known as the cribriform-morular variant of PTC is redefined as cribriform-morular thyroid carcinoma since this tumor is now considered a distinct malignant thyroid neoplasm of uncertain histogenesis. The ‘differentiated high-grade thyroid carcinoma’ is a new diagnostic category including PTCs, follicular thyroid carcinomas and oncocytic carcinomas with high-grade features associated with poorer prognosis similar to the traditionally defined poorly differentiated thyroid carcinoma as per Turin criteria. In addition, squamous cell carcinoma of the thyroid is now considered a morphologic pattern/subtype of anaplastic thyroid carcinoma. In this review, we will highlight the key changes in the newly devised fifth edition of the WHO classification scheme of thyroid tumors with reflections on its applicability in patient management and future directions in this field.

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Nimrod B Kiss Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Andreas Muth Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Adam Andreasson Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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C Christofer Juhlin Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Janos Geli Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Martin Bäckdahl Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Anders Höög Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Bo Wängberg Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Ola Nilsson Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Håkan Ahlman Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Catharina Larsson Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Cancer Centre Karolinska, Department of Surgery, Department of Oncology–Pathology, Department of Pathology, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, SE-171 76 Stockholm, Sweden

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Recurrent alterations in promoter methylation of tumor suppressor genes (TSGs) and LINE1 (L1RE1) repeat elements were previously reported in pheochromocytoma and abdominal paraganglioma. This study was undertaken to explore CpG methylation abnormalities in an extended tumor panel and assess possible relationships between metastatic disease and mutation status. CpG methylation was quantified by bisulfite pyrosequencing for selected TSG promoters and LINE1 repeats. Methylation indices above normal reference were observed for DCR2 (TNFRSF10D), CDH1, P16 (CDKN2A), RARB, and RASSF1A. Z-scores for overall TSG, and individual TSG methylation levels, but not LINE1, were significantly correlated with metastatic disease, paraganglioma, disease predisposition, or outcome. Most strikingly, P16 hypermethylation was strongly associated with SDHB mutation as opposed to RET/MEN2, VHL/VHL, or NF1-related disease. Parallel analyses of constitutional, tumor, and metastasis DNA implicate an order of events where constitutional SDHB mutations are followed by TSG hypermethylation and 1p loss in primary tumors, later transferred to metastatic tissue. In the combined material, P16 hypermethylation was prevalent in SDHB-mutated samples and was associated with short disease-related survival. The findings verify the previously reported importance of P16 and other TSG hypermethylation in an independent tumor series. Furthermore, a constitutional SDHB mutation is proposed to predispose for an epigenetic tumor phenotype occurring before the emanation of clinically recognized malignancy.

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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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Samuel Backman Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

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Klara Johansson Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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

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Peter Stålberg Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

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

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Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long-term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation, respectively. One single case was without apparent driver events and was considered as a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples which may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.

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Luqman Sulaiman Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden
Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden

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Inga-Lena Nilsson Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden

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C Christofer Juhlin Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden
Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden
Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden

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Felix Haglund Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden
Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden

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Anders Höög Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden

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Catharina Larsson Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden
Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden

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Jamileh Hashemi Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden
Medical Genetics Unit, Center for Molecular Medicine, Endocrine Surgery Unit, Department of Oncology-Pathology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden

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In this study, we genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated in our institution during 2005–2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P<0.001). Further analysis of 21 LPTAs revealed low MIB1 proliferation index (0.1–1.5%), MEN1 mutations in five cases, and one HRPT2 (CDC73) mutation. Total or partial loss of parafibromin expression was observed in ten tumors, two of which also showed loss of APC expression. Using array CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%), and loss in 11q (33%). Totally, 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11, and 15q and gains in 3q, 5, 7p, 8p, 16q, 17p, and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes most frequently gain of 5 and loss of chromosome 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r=0.48, P=0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features.

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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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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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