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Primitive neuroectodermal tumors of the cerebral hemispheres in two siblings with TP53 germline mutation
J Reifenberger1, G Janssen, R G Weber
1Department of Dermatology, Heinrich-Heine-Universität, Düsseldorf, Germany.
Insights
A TP53 germline mutation was identified in siblings with brain tumors and their mother with ovarian cancer. This mutation led to homozygous tumor suppressor gene inactivation, causing familial cancer clustering and genomic instability.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Familial cancer clustering, particularly with brain tumors, warrants investigation into underlying genetic predispositions.
- The TP53 tumor suppressor gene plays a critical role in preventing cancer development.
Observation:
- Two siblings developed primitive neuroectodermal tumors (PNETs) and the mother developed ovarian carcinoma.
- Genetic analysis revealed a TP53 germline mutation (codon 213) transmitted from the mother to both children.
- All tumors exhibited homozygous TP53 inactivation due to the germline mutation and loss of the wild-type allele.
Findings:
- The identified TP53 mutation (Arg213Trp) was present in the germline of affected family members and in all analyzed tumors.
- Loss of heterozygosity at 17p confirmed the deletion of the paternal wild-type TP53 allele in both PNETs.
- Comparative genomic hybridization revealed significant chromosomal abnormalities and genomic instability in the PNETs.
Implications:
- This case highlights the critical role of TP53 in familial cancer predisposition and tumor development.
- TP53 germline mutations can lead to diverse and aggressive cancers within a family.
- Understanding the impact of TP53 mutations is crucial for genetic counseling and potential therapeutic strategies.
Abstract:
AWe report on two siblings (brother and sister) who developed cerebral PNETs at the age of 5 years and 6 months, respectively. Both children were treated by operation followed by polychemotherapy. The brother also received cranio-spinal irradiation. Nevertheless, the children died about 12 months and 24 months post-operatively due to extensive cerebral tumor recurrences. Shortly after having lost both of her children, the mother developed an intra-abdominal tumor, which was resected and histologically diagnosed as ovarian carcinoma. Because of this unusual familial clustering of tumors and a positive history of brain tumors and other cancers in several maternal relatives, we analyzed DNA isolated from both PNETs and the ovarian carcinoma as well as constitutional (leukocyte) DNA from the whole family for mutation of the TP53 tumor suppressor gene. This analysis revealed that all tumors were homozygous for a missense mutation at codon 213 (CGA => TGG) resulting in an amino acid exchange from arginine to tryptophane. The same mutation was present in one TP53 allele in the constitutional DNA of the mother and the children, indicating that the mother had transmitted a TP53 germline mutation to both of her children. Analysis of loss of heterozygosity at microsatellite markers from 17p confirmed deletion of the paternal (wild-type) allele in both PNETs. Further investigation of the PNETs by comparative genomic hybridization revealed multiple chromosomal abnormalities. Interestingly, some genomic changes were common to both PNETs, while many others were not, a finding suggesting substantial genomic instability, probably as a consequence of p53 inactivation.