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Identification of a novel PTEN intronic deletion in Li-Fraumeni syndrome and its effect on RNA processing
L T Brown1, E Sexsmith, D Malkin
1Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Ave., M5G 1X8, Toronto, Ontario, Canada.
Abstract:
Germline mutations of the TP53 tumor suppressor gene account for the predisposition to cancer observed in many Li-Fraumeni syndrome (LFS) families. A causative genetic factor in the remaining families that harbor no TP53 mutations remains to be elucidated. The PTEN phosphatase tumor suppressor gene is mutated in human cancers observed in LFS. There also exists some phenotypic overlap in the occurrence of cancers in LFS and Cowden's disease (CD), for which germline PTEN mutations are believed to be responsible. We hypothesized that PTEN may be altered in some TP53-wild-type LFS families. We examined LFS primary patient lymphocytes for PTEN alterations using SSCP and sequence analysis. A novel intronic deletion was found in two unrelated individuals, adjacent to the splice acceptor site of PTEN exon 4. Based on an in vitro mRNA processing assay this alteration is predicted to be a polymorphism. The in vivo effects of this proximal splice site deletion are unknown and a genetic cause for the cancers in these families remains to be elucidated. Germline mutations of PTEN were not detected in other families, suggesting that alterations of this tumor suppressor gene do not account for the cancers observed in the subset of LFS individuals with wild-type germline TP53.
Insights
Germline mutations in TP53 cause Li-Fraumeni syndrome (LFS). Researchers investigated the PTEN gene in TP53-wild-type LFS families, but found no causative mutations, leaving the genetic cause unknown.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome.
- Germline TP53 mutations explain LFS in many families, but the genetic cause remains unknown in TP53-wild-type LFS families.
- Phenotypic overlap exists between LFS and Cowden's disease, associated with germline PTEN mutations.
Purpose of the Study:
- To investigate potential alterations in the PTEN tumor suppressor gene in Li-Fraumeni syndrome (LFS) families with wild-type TP53.
- To determine if PTEN mutations contribute to the hereditary cancer predisposition in these families.
Main Methods:
- Analysis of primary patient lymphocytes from LFS individuals.
- Screening for PTEN alterations using Single-Strand Conformation Polymorphism (SSCP) and DNA sequencing.
- In vitro mRNA processing assays to evaluate the functional impact of identified alterations.
Main Results:
- A novel intronic deletion near the PTEN exon 4 splice acceptor site was identified in two unrelated individuals.
- In vitro assays predicted this deletion to be a common polymorphism, not a disease-causing mutation.
- No other germline PTEN mutations were detected in the studied TP53-wild-type LFS families.
Conclusions:
- Germline PTEN mutations do not appear to be a significant cause of hereditary cancers in TP53-wild-type Li-Fraumeni syndrome families.
- The genetic basis for cancer predisposition in a subset of LFS families with wild-type TP53 remains to be elucidated.
- Further research is needed to identify the causative genetic factors in these families.