Genotype-specific neoplastic risk profiles in patients with VHL disease

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dc.article.numbere240260
dc.catalogadoryvc
dc.contributor.authorGanner, Athina
dc.contributor.authorFerrara, Alfonso Massimiliano
dc.contributor.authorSekula, Peggy
dc.contributor.authorSchiavi, Francesca
dc.contributor.authorJoo, Julia H.
dc.contributor.authorSanso, Gabriela
dc.contributor.authorAlmeida, Madson
dc.contributor.authorKnoblauch, Anna Laura
dc.contributor.authorGizaw, Christine Julia
dc.contributor.authorKrzystolik, Karol
dc.contributor.authorAstheimer, Sophie Charlotte Astheimer
dc.contributor.authorAchatz, María Isabel
dc.contributor.authorVieites, Ana
dc.contributor.authorDonegan, Diane
dc.contributor.authorHundsberger, Thomas
dc.contributor.authorLubinski, Jan
dc.contributor.authorYildirim Simsir, Ilgin
dc.contributor.authorBandgar, Tushar
dc.contributor.authorHasse-Lazar, Kornelia
dc.contributor.authorPawlaczek, Agnieszka
dc.contributor.authorKater, Claudio E.
dc.contributor.authorBaudrand Biggs, René Felipe
dc.contributor.authorAndreescu, Corina E.
dc.contributor.authorUslar Nawrath, Thomas Hermann
dc.contributor.authorIshak, Tada
dc.date.accessioned2025-06-19T22:31:17Z
dc.date.available2025-06-19T22:31:17Z
dc.date.issued2025
dc.description.abstractHereditary 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.
dc.description.funderANID/Fondecyt No. 1190419; ANID/ANILLO ACT210039
dc.fechaingreso.objetodigital2025-06-19
dc.fuente.origenORCID
dc.identifier.doi10.1530/erc-24-0260
dc.identifier.urihttps://doi.org/10.1530/erc-24-0260
dc.identifier.urihttps://europepmc.org/articles/PMC12060576
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/104729
dc.information.autorucEscuela de Medicina; Baudrand Biggs, René Felipe; 0000-0002-8655-4957; 1024
dc.information.autorucEscuela de Medicina; Uslar Nawrath, Thomas Hermann; S/I; 187161
dc.issue.numero5
dc.language.isoen
dc.nota.accesocontenido completo
dc.publisherBioscientifica Ltd.
dc.revistaEndocrine-Related Cancer
dc.rightsacceso abierto
dc.rights.licenseCC BY Atribución Internacional 4.0
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectvon Hippel–Lindau disease
dc.subjectGenotype-phenotype
dc.subjectTumor risk profiles
dc.subjectPersonalized preventive medicine
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.titleGenotype-specific neoplastic risk profiles in patients with VHL disease
dc.typeartículo
dc.volumen32
sipa.codpersvinculados1024
sipa.codpersvinculados187161
sipa.trazabilidadORCID;2025-06-16
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