Genotype-specific neoplastic risk profiles in patients with VHL disease
Issued Date
2025-05-01
Resource Type
ISSN
13510088
eISSN
14796821
Scopus ID
2-s2.0-105004381390
Pubmed ID
40202835
Journal Title
Endocrine Related Cancer
Volume
32
Issue
5
Rights Holder(s)
SCOPUS
Bibliographic Citation
Endocrine Related Cancer Vol.32 No.5 (2025)
Suggested Citation
Ganner A., Ferrara A.M., Sekula P., Schiavi F., Joo J.H., Sanso G., Almeida M.Q., Knoblauch A.L., Gizaw C.J., Krzystolik K., Astheimer S.C., Achatz M.I., Vieites A., Donegan D., Hundsberger T., Lubinski J., Simsir I.Y., Bandgar T., Hasse-Lazar K., Pawlaczek A., Zandee W., Yu K., Kater C.E., Rostomyan L., Qi X.P., Deutschbein T., Remde H., Dallagnol T.N., Yukina M., Baudrand R., Andreescu C.E., Kunavisarut T., Ishak N.D., Guillou Horn X.L., Shutler G., Jovanovic M., Peczkowska M., Calissendorff J., Circosta F., Bugalho M.J., Corssmit E.P.M., Gimm O., Quinkler M., Goldmann A., Fernando S.W., Zovato S., Santana L.S., Freitas-Castro F., Rothermundt C., Zimmermann J., Durmaz A., Aykut A., Vroonen L., Krauss T., Taschner C., Ruf J., Klingler J.H., Gläsker S., Lang S., Bucher F., Agostini H., Jilg C., Schultze-Seemann W., Bausch B., Bergfeld A., Rhein K., Uslar T., Concistrè A., Juhlin C.C., Casali-Da-Rocha J.C., Petramala L., Tsoy U., Grineva E., Fang X.D., Kotsis F., Schaefer T., Links T.P., Makay Ö., Fagundes G.F.C., Ngeow J., Shah N., Opocher G., Barontini M., Larsson C., Januszewicz A., Lima J.V., Wohllk N., Letizia C., Donatini G., Maher E.R., Beltsevich D., Bancos I., Cybulski C., Walz M.K., Köttgen A., Eng C., Neumann H.P.H., Neumann-Haefelin E. Genotype-specific neoplastic risk profiles in patients with VHL disease. Endocrine Related Cancer Vol.32 No.5 (2025). doi:10.1530/ERC-24-0260 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/111201
Title
Genotype-specific neoplastic risk profiles in patients with VHL disease
Author(s)
Ganner A.
Ferrara A.M.
Sekula P.
Schiavi F.
Joo J.H.
Sanso G.
Almeida M.Q.
Knoblauch A.L.
Gizaw C.J.
Krzystolik K.
Astheimer S.C.
Achatz M.I.
Vieites A.
Donegan D.
Hundsberger T.
Lubinski J.
Simsir I.Y.
Bandgar T.
Hasse-Lazar K.
Pawlaczek A.
Zandee W.
Yu K.
Kater C.E.
Rostomyan L.
Qi X.P.
Deutschbein T.
Remde H.
Dallagnol T.N.
Yukina M.
Baudrand R.
Andreescu C.E.
Kunavisarut T.
Ishak N.D.
Guillou Horn X.L.
Shutler G.
Jovanovic M.
Peczkowska M.
Calissendorff J.
Circosta F.
Bugalho M.J.
Corssmit E.P.M.
Gimm O.
Quinkler M.
Goldmann A.
Fernando S.W.
Zovato S.
Santana L.S.
Freitas-Castro F.
Rothermundt C.
Zimmermann J.
Durmaz A.
Aykut A.
Vroonen L.
Krauss T.
Taschner C.
Ruf J.
Klingler J.H.
Gläsker S.
Lang S.
Bucher F.
Agostini H.
Jilg C.
Schultze-Seemann W.
Bausch B.
Bergfeld A.
Rhein K.
Uslar T.
Concistrè A.
Juhlin C.C.
Casali-Da-Rocha J.C.
Petramala L.
Tsoy U.
Grineva E.
Fang X.D.
Kotsis F.
Schaefer T.
Links T.P.
Makay Ö.
Fagundes G.F.C.
Ngeow J.
Shah N.
Opocher G.
Barontini M.
Larsson C.
Januszewicz A.
Lima J.V.
Wohllk N.
Letizia C.
Donatini G.
Maher E.R.
Beltsevich D.
Bancos I.
Cybulski C.
Walz M.K.
Köttgen A.
Eng C.
Neumann H.P.H.
Neumann-Haefelin E.
Ferrara A.M.
Sekula P.
Schiavi F.
Joo J.H.
Sanso G.
Almeida M.Q.
Knoblauch A.L.
Gizaw C.J.
Krzystolik K.
Astheimer S.C.
Achatz M.I.
Vieites A.
Donegan D.
Hundsberger T.
Lubinski J.
Simsir I.Y.
Bandgar T.
Hasse-Lazar K.
Pawlaczek A.
Zandee W.
Yu K.
Kater C.E.
Rostomyan L.
Qi X.P.
Deutschbein T.
Remde H.
Dallagnol T.N.
Yukina M.
Baudrand R.
Andreescu C.E.
Kunavisarut T.
Ishak N.D.
Guillou Horn X.L.
Shutler G.
Jovanovic M.
Peczkowska M.
Calissendorff J.
Circosta F.
Bugalho M.J.
Corssmit E.P.M.
Gimm O.
Quinkler M.
Goldmann A.
Fernando S.W.
Zovato S.
Santana L.S.
Freitas-Castro F.
Rothermundt C.
Zimmermann J.
Durmaz A.
Aykut A.
Vroonen L.
Krauss T.
Taschner C.
Ruf J.
Klingler J.H.
Gläsker S.
Lang S.
Bucher F.
Agostini H.
Jilg C.
Schultze-Seemann W.
Bausch B.
Bergfeld A.
Rhein K.
Uslar T.
Concistrè A.
Juhlin C.C.
Casali-Da-Rocha J.C.
Petramala L.
Tsoy U.
Grineva E.
Fang X.D.
Kotsis F.
Schaefer T.
Links T.P.
Makay Ö.
Fagundes G.F.C.
Ngeow J.
Shah N.
Opocher G.
Barontini M.
Larsson C.
Januszewicz A.
Lima J.V.
Wohllk N.
Letizia C.
Donatini G.
Maher E.R.
Beltsevich D.
Bancos I.
Cybulski C.
Walz M.K.
Köttgen A.
Eng C.
Neumann H.P.H.
Neumann-Haefelin E.
Author's Affiliation
Universidade de São Paulo
Sapienza Università di Roma
Karolinska Institutet
Mayo Clinic
Università degli Studi di Padova
Universität Freiburg
Karolinska Universitetssjukhuset
Leids Universitair Medisch Centrum
Universitair Medisch Centrum Groningen
Universidad de Chile
Linköpings Universitet
Indiana University School of Medicine
Universidade Federal de São Paulo
Pontificia Universidad Católica de Chile
Universitätsklinikum Freiburg
Universitätsklinikum Würzburg
Centre Hospitalier Universitaire de Liege
Siriraj Hospital
Universitair Ziekenhuis Brussel
Pomeranian Medical University in Szczecin
Faculdade de Medicina da Universidade de Lisboa
Centre Hospitalier Universitaire de Poitiers
Klinicki Centar Srbije
Seth GS Medical College and KEM Hospital
Ege University Medical School
Hangzhou Medical College
Lee Kong Chian School of Medicine
Medizinische Fakultät
Facoltà di Medicina e Odontoiatria
Istituto Oncologico Veneto IOV - IRCCS
Taussig Cancer Center
Almazov National Medical Research Centre
Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynała Wyszynskiego
A.C.Camargo Cancer Center
Hospital Sirio-Libanês
Medizinische Hochschule Brandenburg Theodor Fontane
Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch
Endocrinology Research Centre
Kliniken Essen-Mitte
Hospital de Ninos Ricardo Gutierrez
Kantonsspital Winterthur
Städtischen Klinikum Karlsruhe
Aston Medical School
Academic Department of Medical Genetics
Hospital Erasto Gaertner
Endocrinology in Charlottenburg
Medicover Oldenburg MVZ
Ozel Saglik Hospital
Ministry of Internal Affairs Hospital
Cantonal Hospital
Sapienza Università di Roma
Karolinska Institutet
Mayo Clinic
Università degli Studi di Padova
Universität Freiburg
Karolinska Universitetssjukhuset
Leids Universitair Medisch Centrum
Universitair Medisch Centrum Groningen
Universidad de Chile
Linköpings Universitet
Indiana University School of Medicine
Universidade Federal de São Paulo
Pontificia Universidad Católica de Chile
Universitätsklinikum Freiburg
Universitätsklinikum Würzburg
Centre Hospitalier Universitaire de Liege
Siriraj Hospital
Universitair Ziekenhuis Brussel
Pomeranian Medical University in Szczecin
Faculdade de Medicina da Universidade de Lisboa
Centre Hospitalier Universitaire de Poitiers
Klinicki Centar Srbije
Seth GS Medical College and KEM Hospital
Ege University Medical School
Hangzhou Medical College
Lee Kong Chian School of Medicine
Medizinische Fakultät
Facoltà di Medicina e Odontoiatria
Istituto Oncologico Veneto IOV - IRCCS
Taussig Cancer Center
Almazov National Medical Research Centre
Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynała Wyszynskiego
A.C.Camargo Cancer Center
Hospital Sirio-Libanês
Medizinische Hochschule Brandenburg Theodor Fontane
Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch
Endocrinology Research Centre
Kliniken Essen-Mitte
Hospital de Ninos Ricardo Gutierrez
Kantonsspital Winterthur
Städtischen Klinikum Karlsruhe
Aston Medical School
Academic Department of Medical Genetics
Hospital Erasto Gaertner
Endocrinology in Charlottenburg
Medicover Oldenburg MVZ
Ozel Saglik Hospital
Ministry of Internal Affairs Hospital
Cantonal Hospital
Corresponding Author(s)
Other Contributor(s)
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.