{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:58:55Z","timestamp":1762869535173,"version":"3.40.4"},"reference-count":35,"publisher":"Bioscientifica","issue":"5","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["431984000-SFB 1453"],"award-info":[{"award-number":["431984000-SFB 1453"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2019\/15873-6"],"award-info":[{"award-number":["2019\/15873-6"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["1190419"],"award-info":[{"award-number":["1190419"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIHR Cambridge Biomedical Research Centre","award":["NIHR203312"],"award-info":[{"award-number":["NIHR203312"]}]}],"content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,4,9]]},"abstract":"<jats:p>Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel\u2013Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic <jats:italic>VHL<\/jats:italic> germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in \u226530 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma\/paraganglioma in carriers of the most frequent <jats:italic>VHL<\/jats:italic> mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (<jats:italic>n<\/jats:italic> = 19), followed by p.Arg161Ter (<jats:italic>n<\/jats:italic> = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (<jats:italic>P<\/jats:italic> &lt; 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by <jats:italic>VHL<\/jats:italic> mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.<\/jats:p>","DOI":"10.1530\/erc-24-0260","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T16:27:06Z","timestamp":1744216026000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":1,"title":["Genotype-specific neoplastic risk profiles in patients with VHL disease"],"prefix":"10.1530","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6455-5641","authenticated-orcid":true,"given":"Athina","family":"Ganner","sequence":"first","affiliation":[{"name":"Renal Division, Department of Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}]},{"given":"Alfonso Massimiliano","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Familial Cancer Clinics, Veneto Institute of Oncology IOV \u2013 IRCCS, Padua, Italy"}]},{"given":"Peggy","family":"Sekula","sequence":"additional","affiliation":[{"name":"Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center \u2013 University of Freiburg, Freiburg, Germany"}]},{"given":"Francesca","family":"Schiavi","sequence":"additional","affiliation":[{"name":"Familial Cancer Clinics, Veneto Institute of Oncology IOV \u2013 IRCCS, Padua, Italy"}]},{"given":"Julia H","family":"Joo","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute; Department of Medical Genetics and Genomics, Medical Specialties Institute; Taussig Cancer Institute, Cleveland Clinic; and Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA"}]},{"given":"Gabriela","family":"Sanso","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u201cDr C\u00e9sar Bergad\u00e1\u201d (CEDIE) CONICET \u2013 FEI \u2013 Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os \u201cRicardo Guti\u00e9rrez\u201d, Buenos Aires, Argentina"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2957-6148","authenticated-orcid":true,"given":"Madson Q","family":"Almeida","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Endocrinologia Molecular e Celular LIM\/25, Divis\u00e3o de Endocrinologia e Metabologia, Hospital das Cl\u00ednicas, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}]},{"given":"Anna Laura","family":"Knoblauch","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Christine Julia","family":"Gizaw","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Karol","family":"Krzystolik","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ministry of Internal Affairs and Administration Hospital, and The International Hereditary Cancer Centre, Szczecin, Poland"}]},{"given":"Sophie Charlotte","family":"Astheimer","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Maria Isabel","family":"Achatz","sequence":"additional","affiliation":[{"name":"Centro de Oncologia, Hospital S\u00edrio-Liban\u00eas, S\u00e3o Paulo, Brazil"}]},{"given":"Ana","family":"Vieites","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u201cDr C\u00e9sar Bergad\u00e1\u201d (CEDIE) CONICET \u2013 FEI \u2013 Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os \u201cRicardo Guti\u00e9rrez\u201d, Buenos Aires, Argentina"}]},{"given":"Diane","family":"Donegan","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Indiana School of Medicine, Indianapolis, Indiana, USA"}]},{"given":"Thomas","family":"Hundsberger","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Cantonal Hospital, Sankt Gallen, Switzerland"}]},{"given":"Jan","family":"Lubinski","sequence":"additional","affiliation":[{"name":"International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland"}]},{"given":"Ilgin","family":"Yildirim Simsir","sequence":"additional","affiliation":[{"name":"Department of General Surgery; Division of Endocrinology and Metabolism Disorders; and Department of Medical Genetics, Ege University Faculty of Medicine, Izmir, Turkey"}]},{"given":"Tushar","family":"Bandgar","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, King Edward Memorial (KEM) Hospital, Mumbai, India"}]},{"given":"Kornelia","family":"Hasse-Lazar","sequence":"additional","affiliation":[{"name":"Nuclear Medicine and Endocrine Oncology Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland"}]},{"given":"Agnieszka","family":"Pawlaczek","sequence":"additional","affiliation":[{"name":"Department of Genetic and Molecular Diagnostics of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland"}]},{"given":"Wouter","family":"Zandee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Groningen University Medical Center, Groningen, The Netherlands"}]},{"given":"Kai","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA"}]},{"given":"Claudio E","family":"Kater","sequence":"additional","affiliation":[{"name":"Adrenal and Hypertension Unit, Division of Endocrinology, Department of Medicine, Federal University of S\u00e3o Paulo, and Santa Casa Medical School, Sao Paulo, Brazil"}]},{"given":"Liliya","family":"Rostomyan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, CHU de Li\u00e8ge, Domaine Universitaire du Sart-Tilman, Li\u00e8ge, Belgium"}]},{"given":"Xiao-Ping","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Hangzhou Medical College, Hangzhou, China"}]},{"given":"Timo","family":"Deutschbein","sequence":"additional","affiliation":[{"name":"Medicover Oldenburg MVZ, Oldenburg, Germany"},{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}]},{"given":"Hanna","family":"Remde","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}]},{"given":"Tabatha Nakakogue","family":"Dallagnol","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Erasto Gaertner, Curitiba, Brazil"},{"name":"A.C. Camargo Cancer Center, Sao Paulo, Brazil"}]},{"given":"Marina","family":"Yukina","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Endocrinology and Department of Surgery, Endocrinology Research Center, Moscow, Russia"}]},{"given":"Rene","family":"Baudrand","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, CETREN-UC, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago, Chile"}]},{"given":"Corina E","family":"Andreescu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium"}]},{"given":"Tada","family":"Kunavisarut","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand"}]},{"given":"Nur Diana","family":"Ishak","sequence":"additional","affiliation":[{"name":"Cancer Genetics Service, Division of Medical Oncology, National Cancer Center Singapore, and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"}]},{"given":"Xavier","family":"Le Guillou Horn","sequence":"additional","affiliation":[{"name":"Departement of Medical Genetics, CHU de POITIERS, Poitiers, France"}]},{"given":"Gemma","family":"Shutler","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK"}]},{"given":"Milan","family":"Jovanovic","sequence":"additional","affiliation":[{"name":"Clinic for Endocrine Surgery, University Clinical Center of Serbia, and School of Medicine, University of Belgrade, Belgrade, Serbia"}]},{"given":"Mariola","family":"P\u0119czkowska","sequence":"additional","affiliation":[{"name":"National Institute of Cardiology, Department of Hypertension, Warsaw, Poland"}]},{"given":"Jan","family":"Calissendorf","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institute, and Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden"}]},{"given":"Francesco","family":"Circosta","sequence":"additional","affiliation":[{"name":"Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, \u201cSapienza\u201d University of Rome, Rome, Italy"}]},{"given":"Maria Jo\u00e3o","family":"Bugalho","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, CHULN and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]},{"given":"Eleonora P M","family":"Corssmit","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands"}]},{"given":"Oliver","family":"Gimm","sequence":"additional","affiliation":[{"name":"Department of Surgery, and Department of Biomedical and Clinical Sciences, Link\u00f6ping University, Link\u00f6ping, Sweden"}]},{"given":"Marcus","family":"Quinkler","sequence":"additional","affiliation":[{"name":"Endocrinology in Charlottenburg, Berlin, Germany"}]},{"given":"Andrea","family":"Goldmann","sequence":"additional","affiliation":[{"name":"Department of Visceral and Thoracic Sugery, Winterthur Cantonal Hospital, Winterthur, Switzerland"}]},{"given":"Sara","family":"Watutantrige Fernando","sequence":"additional","affiliation":[{"name":"Familial Cancer Clinics, Veneto Institute of Oncology IOV \u2013 IRCCS, Padua, Italy"}]},{"given":"Stefania","family":"Zovato","sequence":"additional","affiliation":[{"name":"Familial Cancer Clinics, Veneto Institute of Oncology IOV \u2013 IRCCS, Padua, Italy"}]},{"given":"Lucas S","family":"Santana","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Endocrinologia Molecular e Celular LIM\/25, Divis\u00e3o de Endocrinologia e Metabologia, Hospital das Cl\u00ednicas, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}]},{"given":"Felipe","family":"Freitas-Castro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Endocrinologia Molecular e Celular LIM\/25, Divis\u00e3o de Endocrinologia e Metabologia, Hospital das Cl\u00ednicas, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}]},{"given":"Christian","family":"Rothermundt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Cantonal Hospital, Sankt Gallen, Switzerland"}]},{"given":"Josa","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Cantonal Hospital, Sankt Gallen, Switzerland"}]},{"given":"Asude","family":"Durmaz","sequence":"additional","affiliation":[{"name":"Department of General Surgery; Division of Endocrinology and Metabolism Disorders; and Department of Medical Genetics, Ege University Faculty of Medicine, Izmir, Turkey"}]},{"given":"Ayca","family":"Aykut","sequence":"additional","affiliation":[{"name":"Department of General Surgery; Division of Endocrinology and Metabolism Disorders; and Department of Medical Genetics, Ege University Faculty of Medicine, Izmir, Turkey"}]},{"given":"Laurent","family":"Vroonen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, CHU de Li\u00e8ge, Domaine Universitaire du Sart-Tilman, Li\u00e8ge, Belgium"}]},{"given":"Tobias","family":"Krauss","sequence":"additional","affiliation":[{"name":"Department of Radiology, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Christian","family":"Taschner","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Juri","family":"Ruf","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, St\u00e4dtisches Klinikum Karlsruhe, Karlsruhe, Germany"}]},{"given":"Jan-Helge","family":"Klingler","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Sven","family":"Gl\u00e4sker","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Stefan","family":"Lang","sequence":"additional","affiliation":[{"name":"Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Department of Ophthalmology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane (MHB), Brandenburg an der Havel, Germany"}]},{"given":"Felicitas","family":"Bucher","sequence":"additional","affiliation":[{"name":"Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}]},{"given":"Hansj\u00fcrgen","family":"Agostini","sequence":"additional","affiliation":[{"name":"Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}]},{"given":"Cordula","family":"Jilg","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Wolfgang","family":"Schultze-Seemann","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Birke","family":"Bausch","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany"}]},{"given":"Antonia","family":"Bergfeld","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}]},{"given":"Kilian","family":"Rhein","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}]},{"given":"Thomas","family":"Uslar","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, CETREN-UC, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago, Chile"}]},{"given":"Antonio","family":"Concistr\u00e8","sequence":"additional","affiliation":[{"name":"Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, \u201cSapienza\u201d University of Rome, Rome, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5945-9081","authenticated-orcid":true,"given":"C Christofer","family":"Juhlin","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden"},{"name":"Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden"}]},{"given":"Jos\u00e9 Cl\u00e1udio","family":"Casali-da-Rocha","sequence":"additional","affiliation":[{"name":"Department of Oncogenetics, A.C. Camargo Cancer Center, Sao Paulo, Brazil"}]},{"given":"Luigi","family":"Petramala","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine, \u201cSapienza\u201d University of Rome, Rome, Italy"}]},{"given":"Uliana","family":"Tsoy","sequence":"additional","affiliation":[{"name":"Neuroendocrinology Laboratory, Endocrinology Institute, Almazov National Medical Research Centre, St. Petersburg, Russia"}]},{"given":"Elena","family":"Grineva","sequence":"additional","affiliation":[{"name":"Neuroendocrinology Laboratory, Endocrinology Institute, Almazov National Medical Research Centre, St. Petersburg, Russia"}]},{"given":"Xu-Dong","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Hangzhou Medical College, Hangzhou, China"}]},{"given":"Fruzsina","family":"Kotsis","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center \u2013 University of Freiburg, Freiburg, Germany"}]},{"given":"Tobias","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}]},{"given":"Thera P","family":"Links","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Groningen University Medical Center, Groningen, The Netherlands"}]},{"given":"\u00d6zer","family":"Makay","sequence":"additional","affiliation":[{"name":"\u00d6zel Sa\u011fl\u0131k Hospital, Centre for Endocrine Surgery, Izmir, Turkey"}]},{"given":"Gustavo F C","family":"Fagundes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Endocrinologia Molecular e Celular LIM\/25, Divis\u00e3o de Endocrinologia e Metabologia, Hospital das Cl\u00ednicas, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1558-3627","authenticated-orcid":true,"given":"Joanne","family":"Ngeow","sequence":"additional","affiliation":[{"name":"Cancer Genetics Service, Division of Medical Oncology, National Cancer Center Singapore, and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"}]},{"given":"Nalini","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, King Edward Memorial (KEM) Hospital, Mumbai, India"}]},{"given":"Giuseppe","family":"Opocher","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, DIMED, University of Padua, Padua, Italy"}]},{"given":"Marta","family":"Barontini","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u201cDr C\u00e9sar Bergad\u00e1\u201d (CEDIE) CONICET \u2013 FEI \u2013 Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os \u201cRicardo Guti\u00e9rrez\u201d, Buenos Aires, Argentina"}]},{"given":"Catharina","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"}]},{"given":"Andrzej","family":"Januszewicz","sequence":"additional","affiliation":[{"name":"National Institute of Cardiology, Department of Hypertension, Warsaw, Poland"}]},{"given":"Jos\u00e9","family":"Viana Lima","sequence":"additional","affiliation":[{"name":"Adrenal and Hypertension Unit, Division of Endocrinology, Department of Medicine, Federal University of S\u00e3o Paulo, and Santa Casa Medical School, Sao Paulo, Brazil"}]},{"given":"Nelson","family":"Wohllk","sequence":"additional","affiliation":[{"name":"Endocrine Section, Hospital del Salvador, Department of Medicine University of Chile, Santiago de Chile, Chile"}]},{"given":"Claudio","family":"Letizia","sequence":"additional","affiliation":[{"name":"Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, \u201cSapienza\u201d University of Rome, Rome, Italy"}]},{"given":"Gianluca","family":"Donatini","sequence":"additional","affiliation":[{"name":"Department of General and Endocrine Surgery, CHU Poitiers, Poitiers, France"}]},{"given":"Eamonn R","family":"Maher","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK"},{"name":"Aston Medical School, Aston University, Birmingham, UK"}]},{"given":"Dmitry","family":"Beltsevich","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Endocrinology and Department of Surgery, Endocrinology Research Center, Moscow, Russia"}]},{"given":"Irina","family":"Bancos","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA"}]},{"given":"Cezary","family":"Cybulski","sequence":"additional","affiliation":[{"name":"International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland"}]},{"given":"Martin K","family":"Walz","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kliniken Essen-Mitte, Essen, Germany"}]},{"given":"Anna","family":"K\u00f6ttgen","sequence":"additional","affiliation":[{"name":"Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center \u2013 University of Freiburg, Freiburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3693-5145","authenticated-orcid":true,"given":"Charis","family":"Eng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute; Department of Medical Genetics and Genomics, Medical Specialties Institute; Taussig Cancer Institute, Cleveland Clinic; and Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA"}]},{"given":"Hartmut P H","family":"Neumann","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}]},{"given":"Elke","family":"Neumann-Haefelin","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Department II of Internal Medicine, Faculty of Medicine, and University Hospital, University of Cologne, Cologne, Germany"}]}],"member":"416","reference":[{"key":"bib2","series-title":"J Roy Stat Soc B Stat Methodol","first-page":"289","article-title":"Controlling the false discovery rate \u2013 a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini Y","year":"1995","unstructured":"Benjamini Y\n & \nHochberg Y\n\n 1995 Controlling the false discovery rate \u2013 a practical and powerful approach to multiple testing. J Roy Stat Soc B Stat Methodol 57 289\u2013300. (https:\/\/doi.org\/10.1111\/j.2517-6161.1995.tb02031.x)"},{"key":"bib3","series-title":"Hum Genet","first-page":"551","article-title":"Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect","volume":"95","author":"Brauch H","year":"1995","unstructured":"Brauch H\n, \nKishida T\n, \nGlavac D\n, et al.\n 1995 Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Hum Genet 95 551\u2013556. (https:\/\/doi.org\/10.1007\/bf00223868)"},{"key":"bib4","series-title":"Hum Mutat","first-page":"1268","article-title":"Large scale genotype- and phenotype-driven machine learning in von Hippel-Lindau disease","volume":"43","author":"Chiorean A","year":"2022","unstructured":"Chiorean A\n, \nFarncombe KM\n, \nDelong S\n, et al.\n 2022 Large scale genotype- and phenotype-driven machine learning in von Hippel-Lindau disease. Hum Mutat 43 1268\u20131285. (https:\/\/doi.org\/10.1002\/humu.24392)"},{"key":"bib5","series-title":"Hum Mol Genet","first-page":"1029","article-title":"Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease","volume":"10","author":"Clifford SC","year":"2001","unstructured":"Clifford SC\n, \nCockman ME\n, \nSmallwood AC\n, et al.\n 2001 Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet 10 1029\u20131038. (https:\/\/doi.org\/10.1093\/hmg\/10.10.1029)"},{"key":"bib6","series-title":"Cancer","first-page":"2927","article-title":"Guidelines for surveillance of patients with von Hippel-Lindau disease: consensus statement of the international VHL surveillance guidelines consortium and VHL alliance","volume":"129","author":"Daniels AB","year":"2023","unstructured":"Daniels AB\n, \nTirosh A\n, \nHuntoon K\n, et al.\n 2023 Guidelines for surveillance of patients with von Hippel-Lindau disease: consensus statement of the international VHL surveillance guidelines consortium and VHL alliance. Cancer 129 2927\u20132940. (https:\/\/doi.org\/10.1002\/cncr.34896)"},{"key":"bib7","series-title":"Hum Mol Genet","first-page":"R187","article-title":"Linking genome variants to disease: scalable approaches to test the functional impact of human mutations","volume":"30","author":"Findlay GM","year":"2021","unstructured":"Findlay GM\n\n 2021 Linking genome variants to disease: scalable approaches to test the functional impact of human mutations. Hum Mol Genet 30 R187\u2013R197. (https:\/\/doi.org\/10.1093\/hmg\/ddab219)"},{"key":"bib8","series-title":"Hum Mutat","first-page":"776","article-title":"Alu-Alu recombination underlies the vast majority of large VHL germline deletions: molecular characterization and genotype-phenotype correlations in VHL patients","volume":"30","author":"Franke G","year":"2009","unstructured":"Franke G\n, \nBausch B\n, \nHoffmann MM\n, et al.\n 2009 Alu-Alu recombination underlies the vast majority of large VHL germline deletions: molecular characterization and genotype-phenotype correlations in VHL patients. Hum Mutat 30 776\u2013786. (https:\/\/doi.org\/10.1002\/humu.20948)"},{"key":"bib9","series-title":"Hum Mutat","first-page":"215","article-title":"Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions","volume":"24","author":"Gallou C","year":"2004","unstructured":"Gallou C\n, \nChauveau D\n, \nRichard S\n, et al.\n 2004 Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions. Hum Mutat 24 215\u2013224. (https:\/\/doi.org\/10.1002\/humu.20082)"},{"key":"bib10","series-title":"Nat Rev Cancer","first-page":"55","article-title":"VHL, the story of a tumour suppressor gene","volume":"15","author":"Gossage L","year":"2015","unstructured":"Gossage L\n, \nEisen T\n & \nMaher ER\n\n 2015 VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15 55\u201364. (https:\/\/doi.org\/10.1038\/nrc3844)"},{"key":"bib11","series-title":"CMAJ","first-page":"133","article-title":"Von Hippel-Lindau disease in a Newfoundland kindred","volume":"134","author":"Green JS","year":"1986","unstructured":"Green JS\n, \nBowmer MI\n & \nJohnson GJ\n\n 1986 Von Hippel-Lindau disease in a Newfoundland kindred. CMAJ 134 133\u2013138."},{"key":"bib12","series-title":"BMJ","article-title":"Sparse data bias: a problem hiding in plain sight","volume":"352","author":"Greenland S","year":"2016","unstructured":"Greenland S\n, \nMansournia MA\n & \nAltman DG\n\n 2016 Sparse data bias: a problem hiding in plain sight. BMJ 352 i1981. (https:\/\/doi.org\/10.1136\/bmj.i1981)"},{"key":"bib13","series-title":"BMJ","article-title":"Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes","volume":"346","author":"Hemingway H","year":"2013","unstructured":"Hemingway H\n, \nCroft P\n, \nPerel P\n, et al.\n 2013 Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes. BMJ 346 e5595. (https:\/\/doi.org\/10.1136\/bmj.e5595)"},{"key":"bib14","series-title":"Hum Mol Genet","first-page":"1019","article-title":"von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF","volume":"10","author":"Hoffman MA","year":"2001","unstructured":"Hoffman MA\n, \nOhh M\n, \nYang H\n, et al.\n 2001 von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10 1019\u20131027. (https:\/\/doi.org\/10.1093\/hmg\/10.10.1019)"},{"key":"bib15","series-title":"Front Genet","first-page":"867","article-title":"Frequent mutations of VHL gene and the clinical phenotypes in the largest Chinese cohort with von Hippel-Lindau disease","volume":"10","author":"Hong B","year":"2019","unstructured":"Hong B\n, \nMa K\n, \nZhou J\n, et al.\n 2019 Frequent mutations of VHL gene and the clinical phenotypes in the largest Chinese cohort with von Hippel-Lindau disease. Front Genet 10 867. (https:\/\/doi.org\/10.3389\/fgene.2019.00867)"},{"key":"bib16","series-title":"N Engl J Med","first-page":"2036","article-title":"Belzutifan for renal cell carcinoma in von Hippel-Lindau disease","volume":"385","author":"Jonasch E","year":"2021","unstructured":"Jonasch E\n, \nDonskov F\n, \nIliopoulos O\n, et al.\n 2021 Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med 385 2036\u20132046. (https:\/\/doi.org\/10.1056\/nejmoa2103425)"},{"key":"bib17","series-title":"Eur J Cancer","article-title":"Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: extended 41-month follow-up in the clear cell renal cell carcinoma cohort","volume":"196","author":"Jonasch E","year":"2024","unstructured":"Jonasch E\n, \nBauer TM\n, \nPapadopoulos KP\n, et al.\n 2024 Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: extended 41-month follow-up in the clear cell renal cell carcinoma cohort. Eur J Cancer 196 113434. (https:\/\/doi.org\/10.1016\/j.ejca.2023.113434)"},{"key":"bib18","series-title":"J Clin Invest","article-title":"Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer","volume":"132","author":"Kaelin WG Jr","year":"2022","unstructured":"Kaelin WG Jr\n\n 2022 Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer. J Clin Invest 132 e162480. (https:\/\/doi.org\/10.1172\/jci162480)"},{"key":"bib19","series-title":"Medicine","first-page":"1","article-title":"von Hippel-Lindau disease affecting 43 members of a single kindred","volume":"68","author":"Lamiell JM","year":"1989","unstructured":"Lamiell JM\n, \nSalazar FG\n & \nHsia YE\n\n 1989 von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine 68 1\u201329. (https:\/\/doi.org\/10.1097\/00005792-198901000-00001)"},{"key":"bib20","series-title":"Lancet","first-page":"2059","article-title":"von Hippel-Lindau disease","volume":"361","author":"Lonser RR","year":"2003","unstructured":"Lonser RR\n, \nGlenn GM\n, \nWalther M\n, et al.\n 2003 von Hippel-Lindau disease. Lancet 361 2059\u20132067. (https:\/\/doi.org\/10.1016\/S0140-6736(03)13643-4)"},{"key":"bib22","series-title":"Curr Genet Med Rep","first-page":"227","article-title":"von Hippel-Lindau disease: an update","volume":"7","author":"Maher ER","year":"2019","unstructured":"Maher ER\n & \nSandford RN\n\n 2019 von Hippel-Lindau disease: an update. Curr Genet Med Rep 7 227\u2013235. (https:\/\/doi.org\/10.1007\/s40142-019-00180-9)"},{"key":"bib21","series-title":"Eur J Hum Genet","first-page":"617","article-title":"von Hippel-Lindau disease: a clinical and scientific review","volume":"19","author":"Maher ER","year":"2011","unstructured":"Maher ER\n, \nNeumann HP\n & \nRichard S\n\n 2011 von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet 19 617\u2013623. (https:\/\/doi.org\/10.1038\/ejhg.2010.175)"},{"key":"bib23","series-title":"Hum Mutat","first-page":"40","article-title":"Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location","volume":"23","author":"Maranchie JK","year":"2004","unstructured":"Maranchie JK\n, \nAfonso A\n, \nAlbert PS\n, et al.\n 2004 Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. Hum Mutat 23 40\u201346. (https:\/\/doi.org\/10.1002\/humu.10302)"},{"key":"bib24","series-title":"Nat Rev Endocrinol","first-page":"233","article-title":"Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas","volume":"13","author":"NGS in PPGL (NGSnPPGL) Study Group","year":"2017","unstructured":"NGS in PPGL (NGSnPPGL) Study Group, \nToledo RA\n, \nBurnichon N\n, \nCascon A\n, et al.\n 2017 Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol 13 233\u2013247. (https:\/\/doi.org\/10.1038\/nrendo.2016.185)"},{"key":"bib25","series-title":"J Clin Oncol","first-page":"2172","article-title":"Von Hippel-Lindau disease: genetics and role of genetic counseling in a multiple neoplasia syndrome","volume":"34","author":"Nielsen SM","year":"2016","unstructured":"Nielsen SM\n, \nRhodes L\n, \nBlanco I\n, et al.\n 2016 Von Hippel-Lindau disease: genetics and role of genetic counseling in a multiple neoplasia syndrome. J Clin Oncol 34 2172\u20132181. (https:\/\/doi.org\/10.1200\/jco.2015.65.6140)"},{"key":"bib26","series-title":"Hum Mutat","first-page":"521","article-title":"Genetic analysis of von Hippel-Lindau disease","volume":"31","author":"Nordstrom-O'Brien M","year":"2010","unstructured":"Nordstrom-O'Brien M\n, \nvan der Luijt RB\n, \nvan Rooijen E\n, et al.\n 2010 Genetic analysis of von Hippel-Lindau disease. Hum Mutat 31 521\u2013537. (https:\/\/doi.org\/10.1002\/humu.21219)"},{"key":"bib27","series-title":"Biometrika","first-page":"99","article-title":"Biometrika centenary: survival analysis","volume":"88","author":"Oakes D","year":"2001","unstructured":"Oakes D\n\n 2001 Biometrika centenary: survival analysis. Biometrika 88 99\u2013142. (https:\/\/doi.org\/10.1093\/biomet\/88.1.99)"},{"key":"bib28","series-title":"Hum Mutat","first-page":"143","article-title":"Genotype-phenotype correlations in von Hippel-Lindau disease","volume":"28","author":"Ong KR","year":"2007","unstructured":"Ong KR\n, \nWoodward ER\n, \nKillick P\n, et al.\n 2007 Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat 28 143\u2013149. (https:\/\/doi.org\/10.1002\/humu.20385)"},{"key":"bib29","series-title":"Front Genet","article-title":"The genotype-phenotype association of von hipple Lindau disease based on mutation locations: a retrospective study of 577 cases in a Chinese population","volume":"11","author":"Qiu J","year":"2020","unstructured":"Qiu J\n, \nZhang K\n, \nMa K\n, et al.\n 2020 The genotype-phenotype association of von hipple Lindau disease based on mutation locations: a retrospective study of 577 cases in a Chinese population. Front Genet 11 532588. (https:\/\/doi.org\/10.3389\/fgene.2020.532588)"},{"key":"bib30","series-title":"Genet Med","first-page":"405","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards S","year":"2015","unstructured":"Richards S\n, \nAziz N\n, \nBale S\n, et al.\n 2015 Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17 405\u2013424. (https:\/\/doi.org\/10.1038\/gim.2015.30)"},{"key":"bib31","series-title":"Science","first-page":"455","article-title":"Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function","volume":"284","author":"Stebbins CE","year":"1999","unstructured":"Stebbins CE\n, \nKaelin WG Jr\n & \nPavletich NP\n\n 1999 Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284 455\u2013461. (https:\/\/doi.org\/10.1126\/science.284.5413.455)"},{"key":"bib32","series-title":"Sci Rep","article-title":"VHLdb: a database of von Hippel-Lindau protein interactors and mutations","volume":"6","author":"Tabaro F","year":"2016","unstructured":"Tabaro F\n, \nMinervini G\n, \nSundus F\n, et al.\n 2016 VHLdb: a database of von Hippel-Lindau protein interactors and mutations. Sci Rep 6 31128. (https:\/\/doi.org\/10.1038\/srep31128)"},{"key":"bib33","series-title":"Hum Mol Genet","first-page":"2046","article-title":"Variant spectrum of von Hippel-Lindau disease and its genomic heterogeneity in Japan","volume":"32","author":"Tamura K","year":"2023","unstructured":"Tamura K\n, \nKanazashi Y\n, \nKawada C\n, et al.\n 2023 Variant spectrum of von Hippel-Lindau disease and its genomic heterogeneity in Japan. Hum Mol Genet 32 2046\u20132054. (https:\/\/doi.org\/10.1093\/hmg\/ddad039)"},{"key":"bib34","series-title":"JAMA Oncol","first-page":"124","article-title":"Association of VHL genotype with pancreatic neuroendocrine tumor phenotype in patients with von Hippel-Lindau disease","volume":"4","author":"Tirosh A","year":"2018","unstructured":"Tirosh A\n, \nSadowski SM\n, \nLinehan WM\n, et al.\n 2018 Association of VHL genotype with pancreatic neuroendocrine tumor phenotype in patients with von Hippel-Lindau disease. JAMA Oncol 4 124\u2013126. (https:\/\/doi.org\/10.1001\/jamaoncol.2017.3428)"},{"key":"bib35","series-title":"Genomics","first-page":"253","article-title":"Comparative sequence analysis of the VHL tumor suppressor gene","volume":"65","author":"Woodward ER","year":"2000","unstructured":"Woodward ER\n, \nBuchberger A\n, \nClifford SC\n, et al.\n 2000 Comparative sequence analysis of the VHL tumor suppressor gene. Genomics 65 253\u2013265. (https:\/\/doi.org\/10.1006\/geno.2000.6144)"},{"key":"bib36","series-title":"Endocrine","first-page":"83","article-title":"Von Hippel-Lindau disease type 2 in a Chinese family with a VHL p.W88X truncation","volume":"48","author":"Zhang M","year":"2015","unstructured":"Zhang M\n, \nWang J\n, \nJiang J\n, et al.\n 2015 Von Hippel-Lindau disease type 2 in a Chinese family with a VHL p.W88X truncation. Endocrine 48 83\u201388. (https:\/\/doi.org\/10.1007\/s12020-014-0368-x)"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/32\/5\/ERC-24-0260.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/32\/5\/ERC-24-0260.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/32\/5\/ERC-24-0260.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T22:20:47Z","timestamp":1745878847000},"score":1,"resource":{"primary":{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/32\/5\/ERC-24-0260.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,9]]},"references-count":35,"journal-issue":{"issue":"5"},"URL":"https:\/\/doi.org\/10.1530\/erc-24-0260","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"type":"print","value":"1351-0088"},{"type":"electronic","value":"1479-6821"}],"subject":[],"published":{"date-parts":[[2025,4,9]]}}}