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Inga-Lena Nilsson
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Jan Zedenius
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Li Yin
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Anders Ekbom
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In order to evaluate the link between primary hyperparathyroidism (pHPT) and malignancies, cases subjected to parathyroid adenomectomy (PTX) during 1958–1997 in Sweden were identified by analyzing the National Swedish Cancer Registry. To minimize the influence of confounding by detection, cases with malignant disease diagnosed before or at the same time as pHPT or during the first year after PTX were excluded. Altogether 9782 cases (7642♀) were included and followed for up to 40 years. Thus, the study comprises 89 571 person-years of observation. The incidence of malignancies was compared with that in the Swedish population standardized for age, sex, and calendar year. An increased overall incidence of cancer was demonstrated in both genders (standardized incidence ratio (SIR) 1.43, 95% confidence interval (CI) 1.35–1.52). This remain unchanged beyond 15 years after PTX. Breast cancer contributed a quarter of the cancer incidence in women (SIR 1.44, 95% CI 1.25–1.62). An increased risk of kidney (SIR 2.40, 95% CI 1.72–3.25), colonic (SIR 1.46, 95% CI 1.19–1.77), and squamous cell skin cancer (SIR 2.79, 95% CI 2.25–3.43) was found in both genders. The risk of endocrine and pancreas cancer was increased in the minority of patients who had their PTX before the age of 40. We conclude that pHPT is associated with an increased risk of developing malignancies that persists even after PTX. This suggests a causal disassociation with the biochemical derangements caused by parathyroid adenoma, while potentially common etiological mechanisms may include genetic predisposition or acquired disability to withstand environmental influence.

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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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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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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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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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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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Tobias Åkerström Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Holger Sven Willenberg Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Kenko Cupisti Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Julian Ip Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Samuel Backman Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Ana Moser Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Rajani Maharjan Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Bruce Robinson Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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K Alexander Iwen Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Henning Dralle Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Cristina D Volpe Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Martin Bäckdahl Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Johan Botling Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Peter Stålberg Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Gunnar Westin Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Martin K Walz Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Hendrik Lehnert Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Stan Sidhu Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Jan Zedenius Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Peyman Björklund Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Per Hellman Department of Surgical Sciences, Department of Endocrinology and Metabolism, General, University of Sydney, Department of Medicine I, Department of General, Department of Molecular Medicine and Surgery, Department of Immunology, Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Uppsala University, Uppsala, Sweden

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Aldosterone-producing adenomas (APAs) are found in 1.5–3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca2 + regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca2 + levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

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