Identification of a Novel Germ Line Variant Hotspot Mutant p53-R175L in Pediatric Adrenal Cortical Carcinoma
Open Access
- 15 May 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (10) , 5056-5062
- https://doi.org/10.1158/0008-5472.can-05-4580
Abstract
Hotspot mutations in the p53 tumor suppressor gene result in the disruption of DNA contact points or alter the overall structure of the protein to prevent DNA binding. When inherited, hotspot mutants are associated with Li-Fraumeni syndrome (LFS), a familial cancer predisposition. One of the most common hotspot mutations occurs at codon 175, resulting in an arginine to histidine substitution. We have identified a novel germ line variant of the 175 mutant (Arg to Leu; R175L) in a pediatric patient who developed adrenal cortical carcinoma. Surprisingly, the family is not tumor prone or associated with LFS. In vitro, the R175L mutant displayed an attenuated tumor suppressor activity in the regulation of transcription, colony formation, and apoptosis when compared with wild-type p53 and the R175H mutant. These findings suggest that p53-R175L retains sufficient activity to suppress LFS, but not adrenal cortical carcinoma. Therefore, not all hotspot mutants are functionally equivalent and the biochemical nature of the mutant may significantly influence clinical outcome. The implications of these results for genetic counseling are discussed. (Cancer Res 2006; 66(10): 5056-62)Keywords
This publication has 24 references indexed in Scilit:
- Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant miceNature Genetics, 2003
- The IARC TP53 database: New online mutation analysis and recommendations to usersHuman Mutation, 2002
- A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramerNature Structural & Molecular Biology, 2001
- An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinomaProceedings of the National Academy of Sciences, 2001
- Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndromeJournal of Medical Genetics, 2001
- Are There Low-Penetrance TP53 Alleles? Evidence from Childhood Adrenocortical TumorsAmerican Journal of Human Genetics, 1999
- Cancer phenotype correlates with constitutional TP53 genotype in families with the Li–Fraumeni syndromeOncogene, 1998
- Crystal Structure of a p53 Tumor Suppressor-DNA Complex: Understanding Tumorigenic MutationsScience, 1994
- WAF1, a potential mediator of p53 tumor suppressionCell, 1993
- Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element.Genes & Development, 1992