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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.
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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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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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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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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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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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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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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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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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.
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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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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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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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.
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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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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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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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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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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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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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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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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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.
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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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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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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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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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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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.
Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden
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Anaplastic thyroid cancer (ATC) is a rare but highly aggressive disease with largely unexplained etiology and molecular pathogenesis. In this study, we analyzed genome-wide copy number changes, BRAF (V-raf sarcoma viral oncogene homolog B1) mutations, and p16 and cyclin D1 expressions in a panel of ATC primary tumors. Three ATCs harbored the common BRAF mutation V600E. Using array-comparative genomic hybridisation (array-CGH), several distinct recurrent copy number alterations were revealed including gains in 16p11.2, 20q11.2, and 20q13.12. Subsequent fluorescence in situ hybridization revealed recurrent locus gain of UBCH10 in 20q13.12 and Cyclin D1 (CCND1) in 11q13. The detection of a homozygous loss encompassing the CDKN2A locus in 9p21.3 motivated the examination of p16 protein expression, which was undetectable in 24/27 ATCs (89%). Based on the frequent gain in 11q13 (41%; n=11), the role of CCND1 was further investigated. Expression of cyclin D1 protein was observed at varying levels in 18/27 ATCs (67%). The effect of CCND1 on thyroid cell proliferation was assessed in vitro in ATC cells by means of siRNA and in thyroid cells after CCND1 transfection. In summary, the recurrent chromosomal copy number changes and molecular alterations identified in this study may provide an insight into the pathogenesis and development of ATC.