A comprehensive functional analysis of TP53 mutations in human leukaemia may refute a working hypothesis - primarily based on mouse studies that missense mutations confer new cancer-causing functions to the p53 tumour suppressor protein.

The study, which has been published in the journal Science, suggests that these mutations exert a "dominant-negative" effect that reduces the cancer-suppressing activity of wild-type p53.

The TP53 gene was discovered 40 years ago and it now known to be the most frequently mutated gene in human cancer. 

Initially, TP53 was mischaracterised as an oncogene but human genetic studies ultimately established that it encodes a tumour suppressor.

But how cancer-associated mutations in TP53 alter the function of wild-type p53 has continued to be the subject of debate.

The vast majority of TP53 mutations across all cancer types are missense mutations, which can result in non-functional or dysfunctional p53.

Based largely on mouse model experiments, it has been hypothesised that certain missense mutations can transform the p53 tumour suppressor into a tumour promoter via so-called oncogenic "gain of function" (GOF) effects.

To explore the functional consequences of p53 mutations, Steffen Boettcher and colleagues performed a comprehensive analysis of TP53 mutations in human myeloid leukaemia.

Using CRISPR/Cas9 gene editing technology, the authors generated isogenic human leukaemia cell lines featuring the most common p53 missense variants.

This isogenic analysis - as well as comprehensive mutational screening, in vivo experiments in mice and an analysis of clinical data - did not support the notion that missense mutations confer new oncogenic functions to the p53 tumour suppressor protein, according to the authors. 

Instead, the authors discovered that the mutations confer either loss of function effects or dominant-negative effects (DNE) that reduce the tumour-supressing efficacy of wild-type p53 in human leukaemia. 

Source: American Association for the Advancement of Science