Investigation of PIN1 as a Genetic Modifier in Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a heterogeneous cancer predisposition syndrome caused by germline mutations in TP53. Some of this phenotypic variability can be explained by presence of oncogenic mutant p53 proteins in patients with missense TP53 mutations. Recent data suggest that the prolyl-isomerase, PIN1, serves a fundamental role in mutant TP53 oncogenic gain-of-function (GOF). We hypothesized that alterations in expression of PIN1, mediated by the promoter SNP(-)842G>C (rs2233678), modify the cancer phenotype of LFS patients. We demonstrate that the PIN1(-)842 GG genotype is associated with increased PIN1 expression at the transcript and protein level. Overexpression of PIN1 selectively enhances the clonogenicity and chemotherapy resistance of LFS fibroblasts harbouring R248Q mutant p53. Concordantly, LFS patients with the PIN1(-)842 GG genotype develop cancer earlier than those with GC/CC genotypes, with a prominent effect in pediatric patients. The GG genotype may also be associated with some predilection for the development of carcinomas.M.Sc.2016-12-21 00:00:0