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Jenny Welander Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden

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Adam Andreasson Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden

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Michael Brauckhoff Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden
Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden

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Martin Bäckdahl Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden

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Catharina Larsson Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden

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Oliver Gimm Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden
Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden

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Peter Söderkvist Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden

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Pheochromocytomas are neuroendocrine tumors arising from the adrenal medulla. While heritable mutations are frequently described, less is known about the genetics of sporadic pheochromocytoma. Mutations in genes involved in the cellular hypoxia response have been identified in tumors, and recently EPAS1, encoding HIF2α, has been revealed to be a new gene involved in the pathogenesis of pheochromocytoma and abdominal paraganglioma. The aim of this study was to further characterize EPAS1 alterations in non-familial pheochromocytomas. Tumor DNA from 42 adrenal pheochromocytoma cases with apparently sporadic presentation, without known hereditary mutations in predisposing genes, were analyzed for mutations in EPAS1 by sequencing of exons 9 and 12, which contain the two hydroxylation sites involved in HIF2α degradation, and also exon 2. In addition, the copy number at the EPAS1 locus as well as transcriptome-wide gene expression were studied by DNA and RNA microarray analyses, respectively. We identified six missense EPAS1 mutations, three in exon 9 and three in exon 12, in five of 42 pheochromocytomas (12%). The mutations were both somatic and constitutional, and had no overlap in 11 cases (26%) with somatic mutations in NF1 or RET. One sample had two different EPAS1 mutations, shown by cloning to occur in cis, possibly indicating a novel mechanism of HIF2α stabilization through inactivation of both hydroxylation sites. One of the tumors with an EPAS1 mutation also had a gain in DNA copy number at the EPAS1 locus. All EPAS1-mutated tumors displayed a pseudo-hypoxic gene expression pattern, indicating an oncogenic role of the identified mutations.

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Janos Geli
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Nimrod Kiss
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Fredrik Lanner
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Theodoros Foukakis
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Natalia Natalishvili
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Olle Larsson
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Per Kogner
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Anders Höög
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Geoffrey J Clark
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Tomas J Ekström
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Martin Bäckdahl
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Filip Farnebo
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Catharina Larsson
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NORE1A (RASSF5) and RASSF1A are newly described Ras effectors with tumour suppressor functions. Both molecules are frequently inactivated in various cancers. In this study, we aimed to explore the potential involvement of NORE1A and RASSF1A in pheochromocytoma and abdominal paraganglioma tumorigenesis. A panel of 54 primary tumours was analysed for NORE1A and RASSF1A mRNA expression by TaqMan quantitative RT-PCR. Furthermore, NORE1A and RASSF1A promoter methylation was assessed by combined bisulphite restriction endonuclease assay and methylation-sensitive Pyrosequencing respectively. The anti-tumorigenic role of NORE1A was functionally investigated in Nore1A-transfected PC12 rat pheochromocytoma cells by fluorescent inhibition of caspase activity and soft agar assays. Significantly suppressed NORE1A and RASSF1A mRNA levels were detected in primary tumours compared with normal adrenal medulla (P<0.001). Methylation of the NORE1A promoter was not observed in primary tumours. On the other hand, 9% (5/54) of the primary tumours examined showed RASSF1A promoter methylation greater than 20% as detected by Pyrosequencing. Methylation of the RASSF1A promoter was significantly associated with malignant behaviour (P<0.05). Transient expression of Nore1a resulted in enhanced apoptosis and impaired colony formation in soft agar. Our study provides evidence that NORE1A and RASSF1A are frequently suppressed in pheochromocytoma and abdominal paraganglioma. Silencing of NORE1A contributes to the transformed phenotype in these tumours.

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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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Theodoros Foukakis
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Arief Gusnanto
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Amy YM Au
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Anders Höög
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Weng-Onn Lui
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Catharina Larsson
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Göran Wallin
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Jan Zedenius
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The diagnosis of follicular thyroid carcinoma (FTC) in the absence of metastasis can only be established postoperatively. Moreover, high-risk FTCs are often not identifiable at the time of diagnosis. In this study, we aimed to identify transcriptional markers of malignancy and high-risk disease in follicular thyroid tumors. The expression levels of 26 potential markers of malignancy were determined in a panel of 75 follicular thyroid tumors by a TaqMan quantitative RT-PCR approach. Logistic regression analysis (LRA) was used for gene selection and generation of diagnostic and prognostic algorithms. An algorithm based on the expression levels of five genes (TERT, TFF3, PPARγ, CITED1, and EGR2) could effectively predict high-risk disease with a specificity of 98.5%. The metastatic potential could be predicted in all four cases with apparently benign or minimally invasive (MI) disease at the time of diagnosis, but poor long-term outcome. In addition, a second model was produced by implementing two genes (TERT and TFF3), which was able to distinguish adenomas from de facto carcinomas. When this model was tested in an independent series of atypical adenomas (AFTA) and MI-FTCs, 16 out of 17 AFTAs were classified as ‘benign’, while MI-FTCs with vascular invasion (sometimes referred to as ‘moderately invasive’) and/or large tumor size tended to classify in the ‘malignant’ group. The reported models can be the foundation for the development of reliable preoperative diagnostic and prognostic tests that can guide the therapeutic approach of follicular thyroid neoplasms with indeterminate cytology.

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Stefano Caramuta Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Linkiat Lee Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Deniz M Özata Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Pinar Akçakaya Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Hong Xie Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Anders Höög Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Jan Zedenius Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Martin Bäckdahl Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Catharina Larsson Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Weng-Onn Lui Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden
Departments of Oncology-Pathology, Molecular Medicine and Surgery, Cancer Center Karolinska (CCK), Department of Breast and Endocrine Surgery, Karolinska Institutet, Stockholm, Sweden

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Deregulation of microRNA (miRNA) expression in adrenocortical carcinomas (ACCs) has been documented to have diagnostic, prognostic, as well as functional implications. Here, we evaluated the mRNA expression of DROSHA, DGCR8, DICER (DICER1), TARBP2, and PRKRA, the core components in the miRNA biogenesis pathway, in a cohort of 73 adrenocortical tumors (including 43 adenomas and 30 carcinomas) and nine normal adrenal cortices using a RT-qPCR approach. Our results show a significant over-expression of TARBP2, DICER, and DROSHA in the carcinomas compared with adenomas or adrenal cortices (P<0.001 for all comparisons). Using western blot and immunohistochemistry analyses, we confirmed the higher expression of TARBP2, DICER, and DROSHA at the protein level in carcinoma cases. Furthermore, we demonstrate that mRNA expression of TARBP2, but not DICER or DROSHA, is a strong molecular predictor to discriminate between adenomas and carcinomas. Functionally, we showed that inhibition of TARBP2 expression in human NCI-H295R ACC cells resulted in a decreased cell proliferation and induction of apoptosis. TARBP2 over-expression was not related to gene mutations; however, copy number gain of the TARBP2 gene was observed in 57% of the carcinomas analyzed. In addition, we identified that miR-195 and miR-497 could directly regulate TARBP2 and DICER expression in ACC cells. This is the first study to demonstrate the deregulation of miRNA-processing factors in adrenocortical tumors and to show the clinical and biological impact of TARBP2 over-expression in this tumor type.

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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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Deniz M Özata Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Stefano Caramuta Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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David Velázquez-Fernández Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Pinar Akçakaya Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Hong Xie Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Anders Höög Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Jan Zedenius Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Martin Bäckdahl Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Catharina Larsson Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Weng-Onn Lui Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Department of Oncology‐Pathology, Department of Breast and Endocrine Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden

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Adrenocortical carcinoma (ACC) is an aggressive tumor showing frequent metastatic spread and poor survival. Although recent genome-wide studies of ACC have contributed to our understanding of the disease, major challenges remain for both diagnostic and prognostic assessments. The aim of this study was to identify specific microRNAs (miRNAs) associated with malignancy and survival of ACC patients. miRNA expression profiles were determined in a series of ACC, adenoma, and normal cortices using microarray. A subset of miRNAs showed distinct expression patterns in the ACC compared with adrenal cortices and adenomas. Among others, miR-483-3p, miR-483-5p, miR-210, and miR-21 were found overexpressed, while miR-195, miR-497, and miR-1974 were underexpressed in ACC. Inhibition of miR-483-3p or miR-483-5p and overexpression of miR-195 or miR-497 reduced cell proliferation in human NCI-H295R ACC cells. In addition, downregulation of miR-483-3p, but not miR-483-5p, and increased expression of miR-195 or miR-497 led to significant induction of cell death. Protein expression of p53 upregulated modulator of apoptosis (PUMA), a potential target of miR-483-3p, was significantly decreased in ACC, and inversely correlated with miR-483-3p expression. In addition, high expression of miR-503, miR-1202, and miR-1275 were found significantly associated with shorter overall survival among patients with ACC (P values: 0.006, 0.005, and 0.042 respectively). In summary, we identified additional miRNAs associated with ACC, elucidated the functional role of four miRNAs in the pathogenesis of ACC cells, demonstrated the potential involvement of the pro-apoptotic factor PUMA (a miR-483-3p target) in adrenocortical tumors, and found novel miRNAs associated with survival in ACC.

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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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