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. 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 the unaffected parent 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.

Novel PTCH1 and concurrent TP53 mutations in four patients with numerous non‐syndromic basal cell carcinomas: The paradigm of oncogenic synergy

“…The same considerations are applicable for nonsense mutations found in the TP53 gene. Many TP53 mutations have been reported as oncogenic drivers in a variety of malignancies, including breast, liver and brain 23‐30 . It is recorded in the ClinVar archive 31 that the TP53 mutations found in our patients, listed in Table 1, are known to be disease causing.…”

“…as oncogenic drivers in a variety of malignancies, including breast, liver and brain. [23][24][25][26][27][28][29][30] It is recorded in the ClinVar archive 31 that the TP53 mutations found in our patients, listed in Table 1, are known to be disease causing.…”

Allele-specific expression: applications in cancer and technical considerations

“…Recent studies have shown that allele-specific mechanisms play a significant role in cancer development. At the germline variant level, several susceptibility variants identified by cancer GWA studies have been shown to have cis-regulatory effects for nearby genes, and there is evidence that this mechanism may also play a role in high-penetrance familial cancer syndromes [ 27 ]. At the somatic mutation level, a significant fraction of tumors have at least one somatically acquired-oncogenic mutation displaying allelic imbalance.…”

“…Furthermore, allele-specific mechanisms have been speculated to play a role in modifying the penetrance of deleterious variants, for example in individuals with Li-Fraumeni syndrome, caused by germline damaging variation in the tumor suppressor gene TP53 [ 27 ]. Buzby et al reported a father-daughter duo where both were heterozygous carriers of a deleterious TP53 Ser241Tyr variant, but only the daughter developed tumors.…”

Unaffected Li-Fraumeni Syndrome Carrier Parent Demonstrates Allele-Specific mRNA Stabilization of Wild-Type TP53 Compared to Affected Offspring

“…Many of these studies have also focused on investigating these cellular responses to UV irradiation mediated by p53 and its mutants in vitro [ 13 , 14 , 15 , 16 , 17 ]. Hence, primary dermal fibroblast (dFb) cultures were established using tissue samples obtained from the affected LFS daughter and her unaffected father to begin comparing their in vitro responses to UV stress in our previous study [ 18 ]. It was hypothesized that the unaffected carrier father may counteract genotoxic stress by means more characteristic of homozygous wild-type TP53 individuals than that of his affected offspring.…”