Genotype-specific neoplastic risk profiles in patients with VHL disease

Genotype-specific neoplastic risk profiles in patients with VHL disease. Ganner, A., Ferrara, A. M., Sekula, P., Schiavi, F., Joo, J. H., Sanso, G., Almeida, M., Knoblauch, A. L., Gizaw, C. J., Krzystolik, K., Astheimer, S. C., Achatz, M. I., Vieites, A., Donegan, D., Hundsberger, T., Lubinski, J., Yildirim Simsir, I., Bandgar, T., Hasse-Lazar, K., Pawlaczek, A., Zandee, W., Yu, K., Kater, C. E., Rostomyan, L., Qi, X., Deutschbein, T., Remde, H., Dallagnol, T. N., Yukina, M., Baudrand, R., Andreescu, C. E., Kunavisarut, T., Ishak, N. D., Le Guillon Horn, X., Shutler, G., Jovanovic, M., Peczkowska, M., Calissendorf, J., Circosta, F., Bugalho, M. J., Corssmit, E. P., Gimm, O., Quinkler, M., Goldmann, A., Watutantrige-Fernando, S., Zovato, S., Santana, L. S., Freitas-Castro, F., Rothermund, C., Zimmermann, J., Durmaz, A., Aycut, A., Vroonen, L., Krauss, T., Taschner, C., Ruf, J., Klingler, J., Gläsker, S., Lang, S., Bucher, F., Agostini, H., Jilg, C., Schultze-Seemann, W., Bausch, B., Philipp, A., Rhein, K., Uslar, T., Concistrè, A., Juhlin, C. C., Casali-da-Rocha, J. C., Petramala, L., Tsoy, U., Grineva, E., Fang, X., Kotsis, F., Schäfer, T., Links, T. P., Makay, O., Fagundes, G. F. C., Ngeow, J., Shah, N., Opocher, G., Barontini, M., Larsson, C., Januszewicz, A., Viana Lima, J., Wohllk, N., Letizia, C., Donatini, G., Maher, E., Beltsevich, D., Bancos, I., Cybulski, C., Walz, M. K., Koettgen, A., Eng, C., Neumann, H. P. H., & Neumann-Haefelin, E. Endocrine-Related Cancer, April, 2025.
doi abstract bibtex

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 1350 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 6 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\textless0.05) 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.

@article{ganner_genotype-specific_2025,
title = {Genotype-specific neoplastic risk profiles in patients with {VHL} disease},
issn = {1479-6821},
doi = {10.1530/ERC-24-0260},
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 1350 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 6 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{\textless}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.},
language = {eng},
journal = {Endocrine-Related Cancer},
author = {Ganner, Athina and Ferrara, Alfonso Massimiliano and Sekula, Peggy and Schiavi, Francesca and Joo, Julia H. and Sanso, Gabriela and Almeida, Madson and Knoblauch, Anna Laura and Gizaw, Christine Julia and Krzystolik, Karol and Astheimer, Sophie Charlotte and Achatz, Maria Isabel and Vieites, Ana and Donegan, Diane and Hundsberger, Thomas and Lubinski, Jan and Yildirim Simsir, Ilgin and Bandgar, Tushar and Hasse-Lazar, Kornelia and Pawlaczek, Agnieszka and Zandee, Wouter and Yu, Kai and Kater, Claudio E. and Rostomyan, Liliya and Qi, Xiao-Ping and Deutschbein, Timo and Remde, Hanna and Dallagnol, Tabatha Nakakogue and Yukina, Marina and Baudrand, René and Andreescu, Corina E. and Kunavisarut, Tada and Ishak, Nur Diana and Le Guillon Horn, Xavier and Shutler, Gemma and Jovanovic, Milan and Peczkowska, Mariola and Calissendorf, Jan and Circosta, Francesco and Bugalho, Maria Joao and Corssmit, Eleonora Pm and Gimm, Oliver and Quinkler, Marcus and Goldmann, Andrea and Watutantrige-Fernando, Sara and Zovato, Stefania and Santana, Lucas S. and Freitas-Castro, Felipe and Rothermund, Christian and Zimmermann, Josa and Durmaz, Asude and Aycut, Ayca and Vroonen, Laurent and Krauss, Tobias and Taschner, Christian and Ruf, Juri and Klingler, Jan-Helge and Gläsker, Sven and Lang, Stefan and Bucher, Felicitas and Agostini, Hansjürgen and Jilg, Cordula and Schultze-Seemann, Wolfgang and Bausch, Birke and Philipp, Antonia and Rhein, Kilian and Uslar, Thomas and Concistrè, Antonio and Juhlin, C. Christofer and Casali-da-Rocha, José Cláudio and Petramala, Luigi and Tsoy, Uliana and Grineva, Elena and Fang, Xu-Dong and Kotsis, Fruzsina and Schäfer, Tobias and Links, Thera P. and Makay, Ozer and Fagundes, Gustavo F. C. and Ngeow, Joanne and Shah, Nalini and Opocher, Giuseppe and Barontini, Marta and Larsson, Catharina and Januszewicz, Andrzej and Viana Lima, José and Wohllk, Nelson and Letizia, Claudio and Donatini, Gianluca and Maher, Eamonn and Beltsevich, Dmitry and Bancos, Irina and Cybulski, Cezary and Walz, Martin K. and Koettgen, Anna and Eng, Charis and Neumann, Hartmut P. H. and Neumann-Haefelin, Elke},
month = apr,
year = {2025},
pmid = {40202835},
pages = {ERC--24--0260},
}

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