Abstract
Most inherited TP53 mutations have been identified in individuals with a family cancer predisposition syndrome, in which the activity of p53 mutants is severely reduced. However, germline p53 mutants in children with ‘sporadic' adrenocortical or choroid plexus tumors exhibit a wide range of functional activity. Here, we demonstrate the occurrence of a complex germline TP53 mutation in two unrelated families with different cancer phenotypes, neither fulfilling the classic criteria for Li-Fraumeni syndrome. The TP53 mutation consists of a duplication of 7 bp in exon 4, resulting in a frame shift and premature stop signal. Haplotype analysis indicated that the mutation arose independently in the two families. Analysis of the DNA secondary structure predicts the TP53 mutation occurred within a hairpin loop. Additional germline complex mutations occurring within the same region of exon 4 have been identified in the IARC database. Our findings suggest that certain TP53 regions are prone to intrinsic genetic alterations, possibly through defects in DNA replication or repair. Further, carriers of the same TP53 mutation can have diverse cancer profiles, illustrating the complexity of genetic counseling and risk prediction.
Highlights
Inherited mutations in the TP53 tumor suppressor gene are associated with susceptibility to cancer.[1]. Most of these mutations have been identified in individuals from families with Li-Fraumeni syndrome (LFS), Li-Fraumeni-like syndrome or TP53-associated malignancies such as pediatric adrenocortical tumors (ACTs)[2,3] and choroid plexus carcinoma.[4,5]
We report a child with ACT who carried a complex, inherited TP53 mutation identical to a mutation previously reported in a young woman with breast cancer from a family that did not fit the strict LFS criteria.[11]
The first family was that of a patient entered into the International Pediatric Adrenocortical Tumor Registry (IPACTR)
Summary
Inherited mutations in the TP53 tumor suppressor gene are associated with susceptibility to cancer.[1]. The tumorigenic effect of such low-penetrance mutants may depend on cooperating age-and tissue-specific genetic changes. Detailed and active life-long genotype/phenotype studies in the families of individuals carrying lowpenetrance mutations may reveal genetic abnormalities and pathways associated with tumorigenesis. We report a child with ACT who carried a complex, inherited TP53 mutation identical to a mutation previously reported in a young woman with breast cancer from a family that did not fit the strict LFS criteria.[11] Detailed haplotype analysis of these families confirmed that the mutation arose independently in each
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
