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

ABSTRACT: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene TP53 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 TP53 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 TP53 mutation detected in the proband and the 6-mo-old daughter was confirmed to be a carrier. Unexpectedly, the germline TP53 mutation was found to be inherited from the unaffected father. We report here the second genetically confirmed case of TP53-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 TP53 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 TP53 mutations should be considered in genetic counseling for cancer risk assessment and family planning.

SUBMITTER: Cotter JA

PROVIDER: S-EPMC5880265 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Cotter Jennifer A JA Szymanski Linda L Karimov Catherine C Boghossian Lara L Margol Ashley A Dhall Girish G Tamrazi Benita B Varaprasathan G Isaac GI Parham David M DM Judkins Alexander R AR Biegel Jaclyn A JA

Cold Spring Harbor molecular case studies 20180402 2

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene TP53 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 TP53 mutation with loss of heterozygosity for the short arm of Chromosome 17 as the second inactivating event in the tumor. There ...[more]

PMID: 29581140

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Project description:BackgroundNon-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC.MethodsFresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdcscid1l2rgtm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate.ResultsThe PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour.ConclusionsWe successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

Dataset Information

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

Publications

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

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