Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors

Irma van de Beek, Iris E. Glykofridis, Anja Wagner, Dorine T. den Toom, Ernie M.H.F. Bongers, Geert J.L.H. van Leenders, Paul C. Johannesma, Hanne E.J. Meijers-Heijboer, Rob M.F. Wolthuis, Maurice A.M. van Steensel, Hendrikus J. Dubbink, Arjan C. Houweling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three family members: Birt-Hogg-Dubé syndrome and Li-Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17. 

Methods: We describe the phenotype and performed single nucleotide polymorphism (SNP)-based loss of heterozygosity (LOH) analysis of the tumors. 

Results: All examined tumors showed somatic loss of the wild-type alleles of both FLCN and TP53. 

Conclusions: We hypothesize that a synergistic effect of both mutations caused the unusual phenotype of childhood renal cell carcinoma in this family. This family emphasizes the importance of further genetic testing if a tumor develops at an unexpected young age in an inherited cancer predisposition syndrome.

Original languageEnglish
Article numbere2098
Number of pages10
JournalMolecular Genetics and Genomic Medicine
Issue number2
Early online date16 Nov 2022
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information: We thank Tom Carney, Monique Luijten, Arnette Wong, Ivo de Vos, Xinhong Lim and Barry Coull for their contributions to the experiments on zebrafish with mutations in both flcn and tp53. The zebrafish experiments mentioned in the discussion were funded by the A*STAR Research Attachment Programme and the Nijbakker Morra stichting.

Publisher Copyright: © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.


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