Citations 2
Genotype-specific neoplastic risk profiles in patients with VHL disease
Ganner, Athina , Sekula, Peggy , Schiavi, Francesca , Joo, Julia H. , Sansó, Gabriela , Almeida, Madson Q. , Knoblauch, Anna Laura, Gizaw, Christine Julia, Krzystolik, Karol , Astheimer, Sophie, Vieites, Ana , Donegan, Diane , Simsir, Ilgin Yildirim , Bandgar, Tushar , Pawlaczek, Agnieszka, Zandee, Wouter T. , Kater, Cláudio E. , Qi, Xiao-Ping , Deutschbein, Timo , Dallagnol, Tabatha Nakakogue , Yukina, Marina, Baudrand, René , Andreescu, Corina , Kunavisarut, Tada , Ishak, Nur Diana Binte , Horn, Xavier Le Guillon, Shutler, Gemma, Jovanović, Milan , Calissendorf, Jan, Circosta, Francesco , Bugalho, Maria João , Corssmit, Eleonora Pm, Goldmann, Andrea , Zovato, Stefania , Santana, Lucas Santos de , Freitas-Castro, Felipe , Rothermund, Christy A, Zimmermann, Josa, Aycut, Ayca, Vroonen, Laurent , Krauß, Tobias , Taschner, Christian , Ruf, Juri , Gläsker, Sven , Bucher, Felicitas , Agostini, Hansjürgen , Jilg, Cordula A. , Schultze‐Seemann, Wolfgang, Bausch, Birke, Bergfeld, Antonia, Rhein, Kilian , Fang, Xu-Dong , Kotsis, Fruzsina , Schäfer, Tobias, Links, Thera P. , Makay, Özer , Fagundes, Gustavo Freitas Cardoso, Shah, Nalini , Barontini, Marta, Larsson, Catharina , Januszewicz, Andrzej , Lima, José Viana , Cybulski, Cezary, Walz, Martin K. , Koettgen, Anna, Neumann, Hartmut P.H., Neumann‐Haefelin, Elke , Köttgen, Anna , Yukina, M. Yu. , Sekula, Peggy , Almeida, Madson Q , Juhlin, Carl Christofer , Ngeow, Joanne , Eng, Charis , Baudrand, Rene , Ferrara, Alfonso Massimiliano , Steiert, Christine , Achatz, Maria Isabel , Hundsberger, Thomas , Lubiński, Jan , Hasse-Lazar, Kornelia , Yu, Kai , Rostomyan, Liliya , Remde, Hanna , Horn, Xavier Le Guillou , Jovanovic, Milan, Pęczkowska, Mariola , Calissendorff, Jan , Gimm, Oliver , Quinkler, Marcus , Watutantrige‐Fernando, Sara , Rothermundt, Christian Alexander , Zimmermann, Josa, Durmaz, Asude , Klingler, Jan‐Helge , Lang, Stefan Johann , Bergfeld, Antonia, Uslar, Thomas , Concistrè, Antonio , Juhlin, C. Christofer , Rocha, José Cláudio Casali da , Petramala, Luigi , Tsoy, U. A. , Grineva, Elena , Fagundes, Gustavo F C , Ngeow, Joanne , Opocher, Giuseppe , Wohllk, Nelson , Letizia, Claudio , Donatini, Gianluca , Maher, Eamonn R. , Beltsevich, D. G. , Bancos, Irina , Eng, Charis
Endocrine-Related Cancer | April 9, 2025 | Volume: 32 | Issue: 5 | Pages: No page available
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.
Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations
Møller, Pål , McCuaig, Jeanna , Eisen, Andrea , Bordeleau, Louise , Zakalik, Dana , Metcalfe, Kelly , Olopade, Olufunmilayo I. , Sun, Ping , Narod, Steven A. , Sweet, Kevin , Elser, Christine , Wiesner, Georgia L. , Poll, Aletta, Kim, Raymond H. , Armel, Susan T., Demsky, Rochelle, Serfas, Kim, Panchal, Seema, Cullinane, Carey A., Reilly, Robert E., Mercer, L J, Dungan, J.S., Lemire, Edmond G., Zovato, Stefania , Rastelli, Antonella, Olopade, Olufunmilayo I , Metcalfe, Kelly A , Eisen, Andrea , Bordeleau, Louise , Kim, Raymond H , Kotsopoulos, Joanne , Gronwald, Jacek , Huzarski, Tomasz , Pal, Tuya , Singer, Christian F. , Karlan, Beth Y. , Aeilts, Amber M. , Eng, Charis , Foulkes, William D. , Tung, Nadine , Couch, Fergus J. , Fruscio, Robert , Neuhausen, Susan L. , Cybulski, Cezary , Lubiński, Jan , Armel, Susan, Steele, Linda, Saal, Howard M. , Rayson, Daniel , Mercer, Leanne, Cajal, Teresa Ramón y , Cohen, Stephanie A.
JAMA Oncology | February 29, 2024 | Volume: 10 | Issue: 4 | Pages: 484
ImportancePreventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined.ObjectiveTo evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation.Design, Setting, and ParticipantsIn this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023.ExposuresSelf-reported bilateral oophorectomy (with or without salpingectomy).Main Outcomes and MeasuresAll-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.ResultsThere were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P &lt; .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P &lt; .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy.Conclusions and RelevanceIn this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.