Transmission of a TP53 germline mutation from unaffected male carrier associated with pediatric glioblastoma in his child and gestational choriocarcinoma in his female partner

• Published in: Cold Spring Harbor molecular case studies 2018-04, Vol.4 (2), p.a002576
• Main Authors: Cotter, Jennifer A, Szymanski, Linda, Karimov, Catherine, Boghossian, Lara, Margol, Ashley, Dhall, Girish, Tamrazi, Benita, Varaprasathan, G Isaac, Parham, David M, Judkins, Alexander R, Biegel, Jaclyn A
• Format: Article
• Language: English
• Subjects: Adult; Biomarkers, Tumor; Biopsy; Child, Preschool; Choriocarcinoma - diagnosis; Choriocarcinoma - etiology; DNA Mutational Analysis; Female; Germ-Line Mutation; Glioblastoma - diagnosis; Glioblastoma - etiology; Heterozygote; Humans; Immunohistochemistry; Li-Fraumeni Syndrome - complications; Li-Fraumeni Syndrome - genetics; Loss of Heterozygosity; Magnetic Resonance Imaging; Male; Pedigree; Research Report; Sex Factors; Tumor Suppressor Protein p53 - genetics
• ISSN: 2373-2865; 2373-2873
• DOI: 10.1101/mcs.a002576

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene LFS is associated with numerous malignancies including astrocytoma. Sanger sequencing and chromosomal microarray studies of blood and tumor tissue from a 4-yr-old boy with glioblastoma demonstrated a germline mutation with loss of heterozygosity for the short arm of Chromosome 17 as the second inactivating event in the tumor. There was no family history of LFS, but the child's mother had recently died from metastatic choriocarcinoma after antecedent normal term delivery of a then 6-mo-old daughter. The choriocarcinoma contained the same mutation detected in the proband and the 6-mo-old daughter was confirmed to be a carrier. Unexpectedly, the germline mutation was found to be inherited from the unaffected father. We report here the second genetically confirmed case of -mutated choriocarcinoma in the partner of an LFS patient. Based on this case and recent literature, female partners of LFS patients may have increased risk of choriocarcinoma due to transmission of germline mutation from male carriers. Although the Toronto protocol has established an effective approach to detect tumors and improve survival in children and adults with LFS, there is a need to expand the current criteria to include surveillance of female partners of LFS patients for choriocarcinoma and other gestational trophoblastic disease. Recognition of this unique mode of transmission of mutations should be considered in genetic counseling for cancer risk assessment and family planning.