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S Felder Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

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H Jann Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

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R Arsenic Institut für Pathologie, Charité – Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany

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T Denecke Klinik für Radiologie, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

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V Prasad Klinik für Nuklearmedizin, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
Klinik für Nuklearmedizin, Universitätklinikum Ulm, Ulm, Germany

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B Knappe-Drzikova Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

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S Maasberg Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
Innere Medizin und Gastroenterologie, Asklepios Klinik St. Georg, Asklepios Medical School, Hamburg, Germany

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B Wiedenmann Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

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M Pavel Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
Medizinische Klinik 1, Gastroenterologie, Pneumologie und Endokrinologie, Universitätsklinikum der Friedrich-Alexander Universität Erlangen, Erlangen, Germany

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A Pascher Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Uinversitätsklinikum Münster, Münster, Germany

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U F Pape Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
Innere Medizin und Gastroenterologie, Asklepios Klinik St. Georg, Asklepios Medical School, Hamburg, Germany

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Introduction Gastric neuroendocrine neoplasias (gNENs) are a heterogeneous subgroup of gastroenteropancreatic neuroendocrine neoplasias (GEP-NENs) derived from specialized cells of the diffuse endocrine system and were initially described as

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Mina Sattari Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

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Annika Kohvakka Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

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Elaheh Moradi A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

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Hanna Rauhala Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

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Henna Urhonen Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

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William B Isaacs The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

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Matti Nykter Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

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Teemu J Murtola Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland
Department of Urology, Tampere University Hospital, Tampere, Finland

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Teuvo L J Tammela Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland
Department of Urology, Tampere University Hospital, Tampere, Finland

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Leena Latonen Foundation for the Finnish Cancer Institute, Helsinki, Finland
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

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G Steven Bova Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

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Juha Kesseli Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

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Tapio Visakorpi Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland
Fimlab Laboratories Ltd, Tampere University Hospital, Tampere, Finland

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Prostate cancer (PCa) is the second-most common cause of male cancer-related death in western industrialized countries, and the emergence of metastases is a key challenge in the treatment of PCa. Accumulating studies have shown that long noncoding RNAs (lncRNAs) play an important role in the regulation of diverse cellular and molecular processes during the development and progression of cancer. Here, we utilized a unique cohort of castration-resistant prostate cancer metastases (mCRPC) and corresponding localized tumors and RNA sequencing (RNA-seq). First, we showed that patient-to-patient variability accounted for most of the variance in lncRNA expression between the samples, suggesting that genomic alterations in the samples are the main drivers of lncRNA expression in PCa metastasis. Subsequently, we identified 27 lncRNAs with differential expression (DE-lncRNAs) between metastases and corresponding primary tumors, suggesting that they are mCRPC-specific lncRNAs. Analyses of potential regulation by transcription factors (TFs) revealed that approximately half of the DE-lncRNAs have at least one binding site for the androgen receptor in their regulatory regions. In addition, TF enrichment analysis revealed the enrichment of binding sites for PCa-associated TFs, such as FOXA1 and HOXB13, in the regulatory regions of the DE-lncRNAs. In a cohort of prostatectomy-treated prostate tumors, four of the DE-lncRNAs showed association with progression-free time and two of them (lnc-SCFD2-2 and lnc-R3HCC1L-8) were independent prognostic markers. Our study highlights several mCRPC-specific lncRNAs that might be important in the progression of the disease to the metastatic stage and may also serve as potential biomarkers for aggressive PCa.

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Paula Fontes Asprino Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil

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Rudinei Diogo Marques Linck Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil
Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, São Paulo, Brazil

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Jônatas Cesar Instituto de Biociências – Universidade de São Paulo (IB-USP), São Paulo, São Paulo, Brazil

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Florêncio Porto Freitas Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil

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Fernanda Christtanini Koyama Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil

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Rachel Simões Pimenta Riechelmann Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, São Paulo, Brazil

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Frederico Perego Costa Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil

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Paulo Marcelo Gehm Hoff Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil
Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, São Paulo, Brazil

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Pedro Alexandre Favoretto Galante Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil

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Diogo Meyer Instituto de Biociências – Universidade de São Paulo (IB-USP), São Paulo, São Paulo, Brazil

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Anamaria Aranha Camargo Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil

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Jorge Sabbaga Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil
Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, São Paulo, Brazil

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Dear Editor, Neuroendocrine neoplasias (NENs) represent a heterogeneous group of diseases with a wide spectrum of morbidity and lethality. These tumors can arise in almost any organ of the body, with the pancreas and the gastrointestinal tract

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Caroline Brain C Brain, Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom of Great Britain and Northern Ireland

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Joanna Grey J Grey, CEO, Association for Multiple Endocrine Neoplasia Disorders, Tonbridge, United Kingdom of Great Britain and Northern Ireland

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Kirstie Purnell K Purnell, Volunteer, Association for Multiple Endocrine Neoplasia Disorders, Leicester, United Kingdom of Great Britain and Northern Ireland

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Multiple endocrine neoplasia type 2 (MEN2) is the collective term for 2 distinct types of autosomal dominantly inherited neuroendocrine neoplasm (NEN) syndromes (Barakat, 2004); MEN2A and MEN 2B (or MEN3). MEN2 is characterised by medullary thyroid cancer (99%) and phaeochromocytoma (50%) but also other conditions according to specific genotype. MEN2A also includes a 25% risk of developing parathyroid hyperplasia and is now recognised as 4 separate syndromes: Classic MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung’s disease (HD) and Familial MTC (Wells, 2015). MEN2B accounts for around 5% of all MEN2 cases and predisposes patients to diffuse intestinal ganglioneuromatosis (Goncharova, 2020), mucosal neuromas, and musculoskeletal abnormalities (Henderson, 2022). MEN2 is autosomal dominantly inherited meaning that several generations in a single family may be affected by the same syndrome. We present a mini review of 4 case studies (x2 MEN2A, x2 MEN2B) that illustrate the advantages of RET testing, as well as some of the likely obstacles that must be overcome to receive a diagnosis of MEN2A or MEN2B. In addition, despite improved genotype/phenotype correlation in MEN2, we highlight that not all cases are ‘typical’ which emphasises the need for all MEN2 patients to be cared for in a centre of expertise and experience. Some of our case study patients or parents also took this opportunity to personally tell us more about their lives with MEN2, illustrating the need for more research into the psychosocial impact of these hereditary diseases.

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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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Dear Editor, The majority of parathyroid tumors are benign, and parathyroid carcinomas represent a diagnostic challenge with limited treatment options. Multiple endocrine neoplasia type 1 gene and cell division cycle 73 ( CDC73 ) are major genes in

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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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Adel Mandl Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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James M Welch Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Gayathri Kapoor Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Vaishali I Parekh Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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David S Schrump Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

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R Taylor Ripley Division of General Thoracic Surgery, Baylor College of Medicine, Houston, Texas, USA

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Mary F Walter NIDDK Clinical Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Jaydira Del Rivero Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

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Smita Jha Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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William F Simonds Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Robert T Jensen Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Lee S Weinstein Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Jenny E Blau Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Sunita K Agarwal Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome (OMIM ID: 131100) carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to the development of various endocrine and non

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Ha Nguyen Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Komal Shah Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Steven G Waguespack Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Mimi I Hu Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Mouhammed Amir Habra Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Maria E Cabanillas Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Naifa L Busaidy Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Roland Bassett Division of Science, Department of Biostatistics, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Shouhao Zhou Division of Science, Department of Biostatistics, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Priyanka C Iyer Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Garrett Simmons Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Diana Kaya Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Marie Pitteloud Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Sumit K Subudhi Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Adi Diab Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Ramona Dadu Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6–3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.

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Kreepa G Kooblall OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Victoria J Stokes OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Omair A Shariq OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Katherine A English OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Mark Stevenson OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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John Broxholme Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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Benjamin Wright Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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Helen E Lockstone Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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David Buck Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah Medical Center and Faculty of Medicine, The Hebrew University of Jerusalem, Israel

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Christopher J Yates OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Rajesh V Thakker OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK

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Kate E Lines OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

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Introduction Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreas and pituitary. Over 90% of patients

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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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