title: Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo.
abstract: A single-nucleotide polymorphism (SNP) in exon 4 results in expression of either arginine (72R) or proline (72P) at codon 72 of p53. We demonstrate that the in vitro response of cells exposed to anticancer agents is strongly influenced by this SNP in wild-type p53. In inducible systems and in cells expressing the endogenous protein, expression of 72P wild-type p53 results in a predominant G1 arrest, with only a minor apoptosis, at drug concentrations causing extensive apoptosis in cells expressing the 72R wild-type variant. The superior apoptosis-inducing activity of the 72R form correlates with more efficient induction of specific apoptosis-associated genes, and is maximal in the presence of serine 46 (S46). In vivo, the outcome of chemo-radiotherapy of squamous carcinomas is more favourable in cancers retaining a wild-type 72R allele, such cases having higher response rates and longer survival than those with wild-type 72P. Together, these results reveal that this SNP is an important determinant of response to anticancer agents in cells expressing wild-type p53. Analysis of complete p53 genotype (mutation and SNP) merits detailed investigation as a simple means for prediction of treatment response and survival in clinical oncology.
authors.affiliation: Ludwig Institute for Cancer Research, Imperial College Faculty of Medicine, St Mary's Hospital, Norfolk Place, London, England.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sullivan
authors.forename: Nelofer
authors.initials: N
authors.lastname: Syed
authors.forename: Milena
authors.initials: M
authors.lastname: Gasco
authors.forename: Daniele
authors.initials: D
authors.lastname: Bergamaschi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trigiante
authors.forename: Marlene
authors.initials: M
authors.lastname: Attard
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Farrell
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Tim
authors.initials: T
authors.lastname: Crook
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016158:Genes, p53; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
chemical_list: D000970:Antineoplastic Agents