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Ravi Kumar Dutta, Jenny Welander, Michael Brauckhoff, Martin Walz, Piero Alesina, Thomas Arnesen, Peter Söderkvist and Oliver Gimm

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Jens Waldmann, Volker Fendrich, Julia Holler, Malte Buchholz, Ernst Heinmöller, Peter Langer, Annette Ramaswamy, Birgit Samans, Martin K Walz, Matthias Rothmund, Detlef K Bartsch and Emily P Slater

The diagnosis of a malignant pheochromocytoma (PC) can only be established by the presence of distant metastases, but a subset of apparently benign PCs develop metastases. We have employed a microarray analysis to identify a typical gene expression profile which distinguishes malignant from benign PC. Total RNA was isolated from fresh-frozen tissue of five benign and five malignant PCs. The reference consisted of laser microdissected tissue from normal adrenal medulla. After generating Cy3- and Cy5-fluorescently labeled cDNAs, F-chips containing 11 540 spots were hybridized. Data were analyzed with the IMAGENE 3.0 software. Gene expression levels were validated by real-time (RT)-PCR and immunohistochemistry (IHC). The analysis revealed a more than twofold difference in expression between benign and malignant PCs in 132 genes: 19 were up-regulated and 113 were down-regulated. Expression differences of six genes (calsequestrin, NNAT, neurogranin, secreted protein acidic and rich in cysteine (SPARC), EGR2, and MAOB) were confirmed by RT-PCR in 25 PCs. IHC for calsequestrin revealed an overexpression in malignant PCs (7/10 vs 1/10, P=0.03). Comparative analysis by microarray of all ten PCs (benign/malignant) versus normal adrenal medulla revealed a more than twofold expression difference in 455/539 and 491/671 genes respectively. Several of these genes are known to participate on adrenal tumorigenesis, potential tumor suppressor genes, and oncogenes. Comprehensive gene expression analysis of malignant and benign PCs revealed different gene profiles, which could be used to discriminate between malignant and benign PCs. Based on these findings, the strategy for further follow-up and treatment could be modified accordingly.

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Tobias Åkerström, Holger Sven Willenberg, Kenko Cupisti, Julian Ip, Samuel Backman, Ana Moser, Rajani Maharjan, Bruce Robinson, K Alexander Iwen, Henning Dralle, Cristina D Volpe, Martin Bäckdahl, Johan Botling, Peter Stålberg, Gunnar Westin, Martin K Walz, Hendrik Lehnert, Stan Sidhu, Jan Zedenius, Peyman Björklund and Per Hellman

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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Birke Bausch, Ulrich Wellner, Dirk Bausch, Francesca Schiavi, Marta Barontini, Gabriela Sanso, Martin K Walz, Mariola Peczkowska, Georges Weryha, Patrizia Dall'Igna, Giovanni Cecchetto, Gianni Bisogno, Lars C Moeller, Detlef Bockenhauer, Attila Patocs, Karoly Rácz, Dmitry Zabolotnyi, Svetlana Yaremchuk, Iveta Dzivite-Krisane, Frederic Castinetti, David Taieb, Angelica Malinoc, Ernst von Dobschuetz, Jochen Roessler, Kurt W Schmid, Giuseppe Opocher, Charis Eng and Hartmut P H Neumann

A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma–Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.

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Hartmut P Neumann, William F Young Jr, Tobias Krauss, Jean-Pierre Bayley, Francesca Schiavi, Giuseppe Opocher, Carsten C Boedeker, Amit Tirosh, Frederic Castinetti, Juri Ruf, Dmitry Beltsevich, Martin Walz, Harald-Thomas Groeben, Ernst von Dobschuetz, Oliver Gimm, Nelson Wohllk, Marija Pfeifer, Delmar M Lourenço Jr, Mariola Peczkowska, Attila Patocs, Joanne Ngeow, Özer Makay, Nalini S Shah, Arthur Tischler, Helena Leijon, Gianmaria Pennelli, Karina Villar Gómez de las Heras, Thera P Links, Birke Bausch and Charis Eng

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

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Frederic Castinetti, Ana Luiza Maia, Mariola Peczkowska, Marta Barontini, Kornelia Hasse-Lazar, Thera P Links, Rodrigo A Toledo, Sarka Dvorakova, Caterina Mian, Maria Joao Bugalho, Stefania Zovato, Maria Alevizaki, Andrei Kvachenyuk, Birke Bausch, Paola Loli, Simona R Bergmann, Attila Patocs, Marija Pfeifer, Josefina Biarnes Costa, Ernst von Dobschuetz, Claudio Letizia, Gerlof Valk, Marcin Barczynski, Malgorzata Czetwertynska, John T M Plukker, Paola Sartorato, Tomas Zelinka, Petr Vlcek, Svetlana Yaremchuk, Georges Weryha, Letizia Canu, Nelson Wohllk, Frederic Sebag, Martin K Walz, Charis Eng and Hartmut P H Neumann

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Tobias Krauss, Alfonso Massimiliano Ferrara, Thera P Links, Ulrich Wellner, Irina Bancos, Andrey Kvachenyuk, Karina Villar Gómez de las Heras, Marina Y Yukina, Roman Petrov, Garrett Bullivant, Laura von Duecker, Swati Jadhav, Ursula Ploeckinger, Staffan Welin, Camilla Schalin-Jäntti, Oliver Gimm, Marija Pfeifer, Joanne Ngeow, Kornelia Hasse-Lazar, Gabriela Sansó, Xiaoping Qi, M Umit Ugurlu, Rene E Diaz, Nelson Wohllk, Mariola Peczkowska, Jens Aberle, Delmar M Lourenço Jr, Maria A A Pereira, Maria C B V Fragoso, Ana O Hoff, Madson Q Almeida, Alice H D Violante, Ana R P Quidute, Zhewei Zhang, Mònica Recasens, Luis Robles Díaz, Tada Kunavisarut, Taweesak Wannachalee, Sirinart Sirinvaravong, Eric Jonasch, Simona Grozinsky-Glasberg, Merav Fraenkel, Dmitry Beltsevich, Viacheslav I Egorov, Dirk Bausch, Matthias Schott, Nikolaus Tiling, Gianmaria Pennelli, Stefan Zschiedrich, Roland Därr, Juri Ruf, Timm Denecke, Karl-Heinrich Link, Stefania Zovato, Ernst von Dobschuetz, Svetlana Yaremchuk, Holger Amthauer, Özer Makay, Attila Patocs, Martin K Walz, Tobias B Huber, Jochen Seufert, Per Hellman, Raymond H Kim, Ekaterina Kuchinskaya, Francesca Schiavi, Angelica Malinoc, Nicole Reisch, Barbara Jarzab, Marta Barontini, Andrzej Januszewicz, Nalini Shah, William F Young Jr, Giuseppe Opocher, Charis Eng, Hartmut P H Neumann and Birke Bausch

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.