title: Allele-specific wild-type TP53 expression in the unaffected carrier parent of children with Li-Fraumeni syndrome.
abstract: Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder where an oncogenic TP53 germline mutation is passed from parent to child. Tumor protein p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Paradoxically, some mutant TP53 carriers remain unaffected, while their children develop cancer within the first few years of life. To address this paradox, response to UV stress was compared in dermal fibroblasts (dFb) from an affected LFS patient vs. their unaffected carrier parent. UV induction of CDKN1A/p21, a regulatory target of p53, in LFS patient dFb was significantly reduced compared to the unaffected parent. UV exposure also induced significantly greater p53[Ser15]-phosphorylation in LFS patient dFb, a reported property of some mutant p53 variants. Taken together, these results suggested that unaffected parental dFb may express an increased proportion of wild-type vs. mutant p53. Indeed, a significantly increased ratio of wild-type to mutant TP53 allele-specific expression in the unaffected parent dFb was confirmed by RT-PCR-RFLP and RNA-seq analysis. Hence, allele-specific expression of wild-type TP53 may allow an unaffected parent to mount a response to genotoxic stress more characteristic of homozygous wild-type TP53 individuals than their affected offspring, providing protection from the oncogenesis associated with LFS.
authors.affiliation: Hematology Research and Advanced Diagnostics Laboratories, CHOC Children's Hospital of Orange County, Orange, CA, USA. Electronic address: jbuzby@choc.org.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Buzby
authors.affiliation: Hematology Research and Advanced Diagnostics Laboratories, CHOC Children's Hospital of Orange County, Orange, CA, USA.
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Williams
authors.affiliation: Next Generation Sequencing and Microarray Core Facility, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Lana
authors.initials: L
authors.lastname: Schaffer
authors.affiliation: Next Generation Sequencing and Microarray Core Facility, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Head
authors.affiliation: Hematology Research and Advanced Diagnostics Laboratories, CHOC Children's Hospital of Orange County, Orange, CA, USA; Division of Hematology, CHOC Children's Hospital of Orange County, Orange, CA, USA; Division of Pediatric Hematology, School of Medicine, University of California at Irvine, Orange, CA, USA.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Nugent
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010290:Parents; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Li–Fraumeni syndrome; UV stress; allele-specific expression; p53; tumor suppression