Are TP53 mutations all alike?

Abstract

TP53 is mutated in 10 to 15% of cases of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and is associated with a previous exposure to cytotoxic therapy, complex cytogenetic abnormalities, and a poor prognosis. Recent data have established the importance of TP53-mutant allele status, the determination of which requires specific genetic testing. Compared with monoallelic disease, multihit TP53-mutant AML/MDS is associated with chromosomal abnormalities and decreased overall survival. Most TP53 mutations are missense mutations that localize to the DNA binding domain. Hot-spot mutations involving residues R175, Y220, G245, R248, R273, or R282 represent approximately 35% of all TP53 missense mutations in AML/MDS. There is evidence that these hot-spot mutations may have dominant negative or gain-of-function properties. Here we review this evidence and discuss its potential impact on patient outcomes and clinical management.