Genotype-specific neoplastic risk profiles in patients with VHL disease

Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel-Lindau 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 VHL 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 ≥30 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 VHL 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 (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL 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.

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Journal
Endocrine Related Cancer
Published
2025-04-09
DOI
https://doi.org/10.1530/erc-24-0260
Primary Topic
Cancer, Hypoxia, and Metabolism
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article
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article

Genotype-specific neoplastic risk profiles in patients with VHL disease

Eleonora Pm Corssmit, Andrea Goldmann, Felipe Freitas-Castro, Mariola Pęczkowska et al.
Endocrine Related Cancer
Cancer, Hypoxia, and Metabolism
article

Genotype-specific neoplastic risk profiles in patients with VHL disease

Eleonora Pm Corssmit, Andrea Goldmann, Felipe Freitas-Castro, Mariola Pęczkowska, Hanna Remde, Xiao-Ping Qi, Christian Taschner, Elena Grineva, Timo Deutschbein, Thomas Uslar, Asude Durmaz, Kilian Rhein, Sven Gläsker, Cláudio E. Kater, Antonia Philipp, Birke Bausch, Francesco Circosta, José Viana Lima, Lucas Santos de Santana, Julia H. Joo, Özer Makay, Ana Vieites, Xu-Dong Fang, Kai Yu, Jan Lubiński, Luigi Petramala, Madson Queiroz Almeida, U. A. Tsoy, Christy A Rothermund, Alfonso Massimiliano Ferrara, Jan‐Helge Klingler, Martin K. Walz, René Baudrand, Irina Bancos, Gabriela Sansó, Kornelia Hasse-Lazar, Charis Eng, Claudio Letizia, Karol Krzystolik, Gianluca Donatini, Giuseppe Opocher, Antonio Concistrè, Hansjürgen Agostini, Andrzej Januszewicz, Oliver Gimm, Francesca Schiavi, Felicitas Bucher, Nur Diana Binte Ishak, Fruzsina Kotsis, Elke Neumann‐Haefelin, Athina Ganner, Wouter T. Zandee, D. G. Beltsevich, Eamonn R. Maher, Tada Kunavisarut, Catharina Larsson, Diane Mary Donegan, Tushar Bandgar, C. Christofer Juhlin, Marta Barontini, Stefania Zovato, Thera P. Links, Juri Ruf, Cordula A. Jilg, Nelson Wohllk, Tabatha Nakakogue Dallagnol, Maria João Bugalho, Stefan J. Lang, Laurent Vroonen, Joanne Ngeow, Peggy Sekula, Thomas Hundsberger, Marcus Quinkler, Liliya Rostomyan, Maria Isabel Achatz, Sara Watutantrige‐Fernando, Sophie Astheimer, Tobias Krauß, Anna Koettgen, Agnieszka Pawlaczek, Corina Andreescu, José Cláudio Casali da Rocha, Wolfgang Schultze‐Seemann, Ilgin Yildirim Simsir, Milan Jovanović, Marina Yukina, Gustavo Freitas Cardoso Fagundes, Nalini Shah, Hartmut P.H. Neumann, J. Zimmermann, Tobias Schäfer, Cezary Cybulski, Anna Laura Knoblauch, Christine Julia Gizaw, Xavier Le Guillon Horn, Gemma Shutler, Jan Calissendorf, Ayca Aycut
article en

Abstract

Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel-Lindau 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 VHL 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 ≥30 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 VHL 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 (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL 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.

Endocrine Related CancerVol. 32(5)
Linköping University (SE), Cleveland Clinic (US), Mayo Clinic (US), Siriraj Hospital (TH), University Medical Center Groningen (NL), Karolinska University Hospital (SE), Vrije Universiteit Brussel (BE), University of Padua (IT), University of Lisbon (PT), Consejo Nacional de Investigaciones Científicas y Técnicas (AR), University of Liège (BE), University of Freiburg (DE), Pontificia Universidad Católica de Chile (CL), Aston University (GB), University of Groningen (NL), Nanyang Technological University (SG), University of St.Gallen (CH), University of Cambridge (GB), Mahidol University (TH), University of Würzburg (DE), Leiden University Medical Center (NL), University Medical Center Freiburg (DE), Erasmus MC (NL), WinnMed (US), Karolinska Institutet (SE), Federal Almazov North-West Medical Research Centre (RU), AC Camargo Hospital (BR), Université de Poitiers (FR), Cleveland Clinic Lerner College of Medicine (US), University of Belgrade (RS), Ege University (TR), Endocrinology Research Center (RU), Städtisches Klinikum Karlsruhe (DE), Hospital del Salvador (CL), Kantonsspital Winterthur (CH), Hospital Erasto Gaertner (BR), Istituto Oncologico Veneto (IT), Centre Hospitalier Universitaire de Poitiers (FR), Centar za Promociju Nauke (RS), 81th Hospital of PLA (CN), National Institute of Oncology (HU), Cancer Clinic (US), Universitätsklinikum Würzburg (DE), Universitair Ziekenhuis Brussel (BE), Sağlık Bilimleri Üniversitesi (TR), College of Medicine & JNM Hospital (IN), Centre Hospitalier Universitaire de Liège (BE), Urology of Indiana (US), Institute of Cardiology (PL), National Cancer Centre Singapore (SG), Medicover (DE), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Kliniken Essen-Mitte (DE), King Edward Memorial Hospital Research Centre (IN), Hospital de Santa Maria (PT), Hospital Sírio-Libanês (BR), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), University Hospital Cologne (DE), Endokrinologikum (DE), Universitätsklinikum Brandenburg an der Havel (DE), Research Center of Neurology (RU), International Hereditary Cancer Center (PL), Hangzhou Medical College (CN), Hospital General de Niños Ricardo Gutierrez (AR), Indiana University – Purdue University Indianapolis (US), University of Chile (CL), Pomeranian Medical University (PL), Sapienza University of Rome (IT), Universidade Federal de São Paulo (BR), Erasmus University Rotterdam (NL)
National Institute for Health and Care Research, European Commission, Deutsche Forschungsgemeinschaft, Fundação de Amparo à Pesquisa do Estado de São Paulo, Agencia Nacional de Investigación y Desarrollo, NIHR Cambridge Biomedical Research Centre
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