p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications

Abstract

The TP53 gene is renowned as a tumor suppressor, playing a pivotal role in overseeing the cell cycle, apoptosis, and maintaining genomic stability. Dysregulation of p53 often contributes to the initiation and progression of various cancers, including lung cancer (LC) subtypes. The review explores the intricate relationship between p53 and its role in the development and progression of LC. p53, a crucial tumor suppressor protein, exists in various isoforms, and understanding their distinct functions in LC is essential for advancing our knowledge of this deadly disease. This review aims to provide a comprehensive literature overview of p53, its relevance to LC, and potential clinical applications.

Keywords: lung cancer subtypes; lung carcinoma; lung squamous cell carcinoma; mutated p53; p53; squamous cell carcinoma.

Figure 1

Summary overview of the p53 pathway. In normal conditions (right panel), the p53 protein is strongly negatively regulated by MDM2/MDMX, an E3 ligase that ubiquitinates p53, leading to its degradation in the proteasome. Under stress conditions, generated by extracellular and intracellular stress (left panel), p53 levels increase, and through post-translational modifications (e.g., phosphorylation, acetylation, and methylation), p53 is activated and stabilized. In the cell nucleus, p53 tetramers bind to DNA through p53 response elements (p53REs), regulating the transcription of genes that control various biological processes.

Figure 2

Genetic alterations of p53 in the different types of lung cancer from cBioPortal datasets. (a) Distribution of p53 mutation type in LUAD (N = 221), NSCLC (N = 240), SCLC (N = 110), and LUSC (N = 175). (b) Point mutations within the p53 gene in LUSC patients. Green, red, and violet boxes correspond to transactivation domain, DNA-binding domain, and oligomerization domain, respectively.

Figure 3

Mutant p53 in cancer. Mutations of p53 can lead to various oncogenic effects, referred to as GOF, among which are metabolic adaptations, genomic instability, tumorigenesis, metastasis, and increased resistance to anticancer treatments. Negative dominant effects on the wild-type protein as well as LOF of the wild-type p53 protein include promoting proliferation, survival, and conferring metastatic potential to cells.

Figure 4

Relation of TP53 gene expression in LUSC patients from cBioPortal datasets with RAP1A gene expression (a) and RHOC gene expression (b).