Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo.
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.
Sullivan
Alexandra
A
Ludwig Institute for Cancer Research, Imperial College Faculty of Medicine, St Mary's Hospital, Norfolk Place, London, England.
Syed
Nelofer
N
Gasco
Milena
M
Bergamaschi
Daniele
D
Trigiante
Giuseppe
G
Attard
Marlene
M
Hiller
Louise
L
Farrell
Paul J
PJ
Smith
Paul
P
Lu
Xin
X
Crook
Tim
T
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
D000970:Antineoplastic Agents