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S Fontanière
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J Tost
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A Wierinckx
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J Lachuer
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J Lu
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N Hussein
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F Busato
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I Gut
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Z-Q Wang
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C-X Zhang
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Mutations of the MEN1 gene lead to the occurrence of multiple endocrine neoplasia type 1 (MEN1). To gain insights into the mechanisms of the tumorigenesis related to MEN1 inactivation, we have used mice in which the Men1 gene was specifically disrupted in pancreatic β-cells. In these mice, we observed full penetrance of insulinoma with defined histological characteristics of tumorigenesis. To identify the genetic factors taking part in the tumour development, we performed gene expression profiling analysis of these insulinomas at different stages. Here, we show that in late stage insulinomas, 56 genes are up-regulated and 194 are down-regulated more than fourfold compared with normal pancreatic islets. Clustering analysis reveals the deregulation of Hox gene family and the genes involved in cell proliferation and cell cycle control. The altered expression of Igf2, Igfbp3 and Igfbp6 as well as cyclin A2, B2 and D2 are confirmed by quantitative RT-PCR, with the overexpression of all the three cyclins found in early stage insulinomas. Moreover, an increased proportion of cyclin A2- and D2-expressing cells and the overexpression of insulin-like growth factor 2 (IGF2) protein are detected in mouse Men1 insulinomas by immunostaining. Interestingly, the analysis of DNA methylation patterns by quantitative serial pyrosequencing reveals that four specific CpGs in the intragenic differentially methylated region 2 (DMR2) region of the Igf2 gene known to augment transcription through methylation are significantly hypermethylated in insulinomas of Men1 β-cell mutant mice at 6 and 10 months of age, even before IGF2 overexpression can be detected. Thus, our data indicate the involvement of both genetic and epigenetic mechanisms in early tumorigenesis of β-cells related to MEN1 inactivation.

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M Principe Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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M Chanal Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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V Karam Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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A Wierinckx Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France
ProfilXpert, Lyon, France

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I Mikaélian Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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R Gadet Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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C Auger Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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V Raverot Laboratoire d’Hormonologie, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France

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E Jouanneau Service de Neurochirurgie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
Faculté de Médecine Lyon Est, Université Lyon 1, Lyon, France

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A Vasiljevic Faculté de Médecine Lyon Est, Université Lyon 1, Lyon, France
Department of Pathology, Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France

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A Hennino Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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G Raverot Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France
Department of Pathology, Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France
Department of Endocrinology, Reference Center for Rare Pituitary Disease (HYPO), Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France

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P Bertolino Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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Prolactinoma represents the most frequent hormone-secreting pituitary tumours. These tumours appear in a benign form, but some of them can reach an invasive and aggressive stage through an unknown mechanism. Discovering markers to identify prolactinoma proliferative and invading character is therefore crucial to develop new diagnostic/prognostic strategies. Interestingly, members of the TGFβ-Activin/BMP signalling pathways have emerged as important actors of pituitary development and adult function, but their role in prolactinomas remains to be precisely determined. Here, using a heterotopic allograft model derived from a rat prolactinoma, we report that the Activins orphan type I receptor ALK7 is ectopically expressed in prolactinomas-cells. Through immunohistological approaches, we further confirm that normal prolactin-producing cells lack ALK7-expression. Using a series of human tumour samples, we show that ALK7 expression in prolactinomas cells is evolutionary conserved between rat and human. More interestingly, our results highlight that tumours showing a robust expression of ALK7 present an increased proliferation as address by Ki67 expression and retrospective analysis of clinical data from 38 patients, presenting ALK7 as an appealing marker of prolactinoma aggressiveness. Beside this observation, our work pinpoints that the expression of prolactin is highly heterogeneous in prolactinoma cells. We further confirm the contribution of ALK7 in these observations and the existence of highly immunoreactive prolactin cells lacking ALK7 expression. Taken together, our observations suggest that Activin signalling mediated through ALK7 could therefore contribute to the hormonal heterogeneity and increased proliferation of prolactinomas.

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S L Asa Department of Pathology and Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University Health Network, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

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O Casar-Borota Department of Pathology, Uppsala University Hospital, Uppsala, Sweden

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P Chanson Service of Endocrinology and Reproductive Diseases, Bicêtre Hospital, Paris, France

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E Delgrange Department of Medicine, University of Louvain, Mont-sur-Meuse, Belgium

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P Earls Department of Anatomical Pathology, St Vincent’s Hospital, Sydney, Australia

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S Ezzat Department of Medicine and Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario, Canada

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A Grossman Department of Endocrinology, University of Oxford, Oxford, UK

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H Ikeda Research Institute for Pituitary Disease, Southern Tohoku General Hospital, Fukushima, Japan

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N Inoshita Department of Pathology, Toranomon Hospital, Tokyo, Japan

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N Karavitaki Department of Endocrinology, Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK

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M Korbonits Division of Endocrinology, Queen Mary Hospital, Barts and the London School of Medicine, London, UK

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E R Laws Jr Department of Neurosurgery, Harvard Medical School, Brigham & Women’s Hospital, Boston, Massachusetts, USA

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M B Lopes Departments of Pathology and Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA

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N Maartens Department of Neurosurgery, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia

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I E McCutcheon Department of Neurosurgery, UT MD Anderson Cancer Center, Houston, Texas, USA

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

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H Nishioka Department of Neurosurgery, Toranomon Hospital, Tokyo, Japan

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G Raverot Department of Endocrinology, Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France

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F Roncaroli Department of Neuropathology, Imperial College, London, UK

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W Saeger Institute of Neuropathology of the University of Hamburg, Hamburg, Germany

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L V Syro Department of Neurosurgery, Hospital Pablo Tobon Uribe, Medellin, Colombia

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A Vasiljevic Department of Pathology, Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France

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C Villa Department of Pathology, Hôpital Foch, Suresnes, France

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A Wierinckx INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France

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J Trouillas Faculty of Medicine Lyon-Est, University of Lyon, Lyon, France

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and the attendees of 14th Meeting of the International Pituitary Pathology Club, Annecy, France, November 2016
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The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

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