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

• Published in: Molecular genetics & genomic medicine Vol. 11; no. 2; pp. e2098 - n/a
• Main Authors: Beek, Irma, Glykofridis, Iris E., Wagner, Anja, Toom, Dorine T., Bongers, Ernie M. H. F., Leenders, Geert J. L. H., Johannesma, Paul C., Meijers‐Heijboer, Hanne E. J., Wolthuis, Rob M. F., Steensel, Maurice A. M., Dubbink, Hendrikus J., Houweling, Arjan C.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2023; John Wiley and Sons Inc; Wiley
• Subjects: Age; Birt‐Hogg‐Dubé syndrome; Brain; Brain cancer; Brain Neoplasms; Brain tumors; Cancer; Carcinoma, Renal Cell - genetics; Children; Chromosome 17; Connective tissue; Gene polymorphism; Genes; Genetic Predisposition to Disease; Genetic screening; Genetic testing; Germ Cells - metabolism; Germ Cells - pathology; Heterozygosity; Humans; Kidney cancer; Kidney Neoplasms - genetics; Li-Fraumeni syndrome; Loss of heterozygosity; Mutation; Nucleotides; Original; p53 Protein; Patients; Phenotypes; Polymorphism; Proto-Oncogene Proteins - genetics; Renal cell carcinoma; Single-nucleotide polymorphism; Surveillance; Synergistic effect; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - genetics; Tumors; renal cell carcinoma; loss of heterozygosity; Birt-Hogg-Dubé syndrome; Li-Fraumeni syndrome
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.2098

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. We describe a family with both Birt‐Hogg‐Dubé syndrome and Li‐Fraumeni syndrome, causing an exceptional phenotype of childhood renal cell carcinoma and brain tumors. All examined tumors showed somatic loss of the wild‐type alleles of FLCN and TP53, which are both located on chromosome 17p.