Unaffected Li-Fraumeni Syndrome Carrier Parent Demonstrates Allele-Specific mRNA Stabilization of Wild-Type Compared to Affected Offspring.

Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder where an oncogenic germline mutation is inherited by offspring of a carrier parent. p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Unexpectedly, some mutant carriers remain unaffected, while their children develop cancer early in life. To begin unravelling this paradox, the response of dermal fibroblasts (dFb) isolated from a child with LFS was compared to those from her unaffected father after UV exposure. Phospho-Chk1[S345], a key activator of cell cycle arrest, was increased by UV induction in the LFS patient compared to their unaffected parent dFb. This result, along with previous findings of reduced /p21 UV induction in affected dFb, suggest that cell cycle dysregulation may contribute to cancer onset in the affected LFS subject but not the unaffected parent. Mutant p53 protein and its promoter binding affinity were also higher in dFb from the LFS patient compared to their unaffected parent. These results were as predicted based on decreased mutant allele-specific mRNA expression previously found in unaffected dFb. Investigation of the potential mechanism regulating this allele-specific expression found that, while epigenetic promoter methylation was not detectable, wild-type mRNA was specifically stabilized in the unaffected dFb. Hence, the allele-specific stabilization of wild-type mRNA may allow an unaffected parent to counteract genotoxic stress by means more characteristic of homozygous wild-type individuals than their affected offspring, providing protection from the oncogenesis associated with LFS.