p53 Mutations in Small Cell Lung Cancer
p53 is a transcription factor involved in a large variety of anti-tumour functions. The importance of p53 in cancer is clear as it is by far the most frequently mutated gene in all human cancers with a frequency across all cancers of over 50% and in certain cancers such as small cell lung cancer (SCLC) reaching more than 90%.
Mutations in TP53 can result in the loss of p53 expression, but can also generate a mutated p53 protein. These mutations cause an impairment or loss of wild type (WT) function dependent on the mutation. When co-expressed with WT p53, mutant p53 proteins can exert a dominant negative function over WT p53. Additionally, mutant p53 has been shown to acquire novel functions and promote tumourigenesis, chemoresistance and metastasis. This oncogenic function of mutant p53 that is independent of any remaining wild type p53 expression was termed Gain-Of-Function (GOF). Different mutant p53 proteins use several strategies to exert GOF, including hijacking other transcription factors, altering protein function of binding partners or binding to DNA both specifically and a-specifically.
In cancers almost every amino acid of p53 has been found mutated making mutant p53 not simply one protein but a large variety of proteins that are likely to have similarities, but also differences in function. Some mutant p53 proteins will have a GOF, whereas others will have a partial/full loss of WT function or dominant negative activity. Most likely all of these, alone or in combination, can contribute to the oncogenic effects of mutant p53 seen in cancers, dependent on the circumstances and selective advantages of the tumour.
Despite the large number of mutations found in p53, there are currently no therapeutic strategies based on p53 status. This potentially is caused by the fact that so many different mutations occur that could all respond different to chemotherapy.
The aim of this project will be to characterize the difference in p53 mutations that occur in SCLC. We will generate a cDNA library with a large number of p53 mutations and test in cells using semi-automatic screening whether p53 mutant proteins are GOF, whether any WT function is remaining or whether a mutant is dominant negative over WT p53 or a combination of any of these. In the meantime we will collect as much information as possible on p53 mutations and patient response to chemotherapy to determine whether a correlation exists between p53 mutations in patients and in vitro. This project could therefore provide vital information to develop therapeutic strategies based on p53 status in the future.