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  • Author: Liborio Torregrossa x
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Cristina Romei Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Teresa Ramone Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Chiara Mulè Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Alessandro Prete Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Virginia Cappagli Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Loredana Lorusso Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Liborio Torregrossa Department of Surgical, Medical, Molecular Pathology, University of Pisa, Pisa, Italy

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Fulvio Basolo Department of Surgical, Medical, Molecular Pathology, University of Pisa, Pisa, Italy

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Raffaele Ciampi Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Rossella Elisei Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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A statistically significant higher prevalence of the RET p.Met918Thr somatic mutation, identified by direct sequencing, was previously reported in MTC > 2 cm than in smaller tumors. Aim of this study was to correlate the full RET and RAS mutation profile, identified by a Next Generation Sequencing approach, with the growth rate, proliferation and tumor size of MTC. Data of 149 sporadic MTC patients were correlated with RET mutations and Ki67 positivity. Eighty-one cases had a somatic RET mutation, 40 had a RAS mutation and 28 were negative. A statistically significant higher prevalence of RET mutations was found in MTC > 2 cm. A higher prevalence of RET more aggressive mutations, higher allelic frequencies and, higher percentage of Ki67 positive cells were found in larger tumors which had also a worse outcome. Our study highlights the predominant role of RET somatic mutations in MTC tumorigenesis. We demonstrate that RET mutation prevalence and allelic frequency (AF) are significantly higher in larger tumors. Based on these results, we can conclude that RET mutated C-cells’s growth and proliferation are more rapid than those of non-mutated cells and give origin to bigger and more aggressive MTC.

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Elena Pardi Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Stefano Mariotti Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Natalia S Pellegata Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Katiuscia Benfini Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Simona Borsari Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Federica Saponaro Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Liborio Torregrossa Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Antonello Cappai Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Chiara Satta Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Marco Mastinu Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Claudio Marcocci Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Filomena Cetani Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Inactivating germline mutations of the CDKN1B gene encoding the nuclear cyclin-dependent kinase inhibitor P27kip1 protein have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to characterize in vitro the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by primary hyperparathyroidism due to multiglandular parathyroid involvement and gastro–entero–pancreatic tumors. We carried out subcellular localization experiments by transfection with plasmid vectors expressing the WT or mutant CDKN1B cDNA into the eukaryotic human cervix adenocarcinoma (HeLa) and GH3 cell lines. Results from western blotting studies indicated that fusion proteins were expressed at equal levels. The mutated protein was shorter compared with the WT protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells, WT P27 localized in the nucleus, whereas the P27_S125X protein was retained in the cytoplasm, predicting the loss of tumor-suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, because both WT and mutant alleles were determined to be present by sequencing the somatic DNA. Immunohistochemistry revealed a complete loss of nuclear expression of P27 in a parathyroid adenoma, which had been removed by the second surgery in the patient. In conclusion, our results confirm the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.

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Filomena Cetani Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Chiara Banti Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Elena Pardi Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Simona Borsari Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Paolo Viacava Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Paolo Miccoli Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Liborio Torregrossa Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Fulvio Basolo Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Maria Rosa Pelizzo Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Massimo Rugge Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Gianmaria Pennelli Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Guido Gasparri Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Mauro Papotti Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Marco Volante Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Edda Vignali Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Federica Saponaro Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Claudio Marcocci Department of Clinical and Experimental Medicine, Section of Pathology, Department of Surgical, Surgery Unit, Medicine, General Surgery 3 and Esophageal Surgery, Clinical and Biological Sciences, Department of Oncology

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Inactivating mutations of the CDC73 tumor suppressor gene have been reported in parathyroid carcinomas (PC), in association with the loss of nuclear expression of the encoded protein, parafibromin. The aim of this study was to further investigate the role of the CDC73 gene in PC and evaluate whether gene carrier status and/or the loss of parafibromin staining might have an effect on the outcome of the disease. We performed genetic and immunohistochemical studies in parathyroid tumor samples from 35 patients with sporadic PC. Nonsense or frameshift CDC73 mutations were detected in 13 samples suitable for DNA sequencing. Six of these mutations were germline. Loss of parafibromin expression was found in 17 samples. The presence of the CDC73 mutation as well as the loss of parafibromin predicted a high likelihood of subsequent recurrence and/or metastasis (92.3%, P=0.049 and 94.1%, P=0.0017 respectively), but only the latter was associated with a decreased overall 5- and 10-year survival rates (59%, P=0.107, and 23%, P=0.0026 respectively). The presence of both the CDC73 mutation and loss of parafibromin staining compared with their absence predicted a lower overall survival at 10- (18 vs 84%, P=0.016) but not at 5-year follow-up. In conclusion, loss of parafibromin staining, better than CDC73 mutation, predicts the clinical outcome and mortality rate. The added value of CDC73 mutational analysis is the possibility of identifying germline mutations, which will prompt the screening of other family members.

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