Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair

Abstract

Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.

Keywords: biomarker; cell death; chemotherapy; gastric cancer; immunotherapy; isoforms; metastasis; p53 family; personalized therapy; tumor ecosystem.

Figure 1

Histological and molecular subgroups of gastric cancer. Gastric cancer has two major histological subtypes: the intestinal subtype (upper left) that presents differentiated cancer cell structures in glands, and the diffuse subtype (lower left) that displays undifferentiated cancer cells dispersed within the stroma. There are also four molecular subgroups defined by the TCGA: the Chromosome instable (CIN), the Genetic Stable (GS), the Microsatellites Instable (MSI), and the Epstein–Barr Virus (EBV) subgroups. Each are characterized by specific deregulated mechanisms. Of note is the two molecular subgroups that tend to respond the best to immunotherapy, the MSI and the EBV subgroups.

Figure 2

The isoforms of the p53 family. The p53 family has 3 genes: TP53, TP63, and TP73, that express multiple isoforms via alternative promoters (P1, P1′, and P2), generating full-length proteins with N-terminus transactivation domains (e.g., TA) or without (e.g., ∆N) and alternative splicing generating variations in the C-terminus (e.g., α, β, and γ). The encoded proteins contain transactivation domains (TAD1, 2, and 3); a proline-rich region (PRD); a DNA-binding domain (DBD), tetramerization domain (TD), sterile α domain (SAM), and an inhibitor domain (ID).

Figure 3

Deregulation affecting the isoforms of the p53 family in gastric cancer. Mutations in TP53 or alterations in the expression of TP53, TP63, and TP73 isoforms are observed during gastric tumorigenesis, evolving from a normal stomach epithelium toward adenocarcinomas via gastritis, metaplasia, and dysplasia. Images taken 20X.

Figure 4

Signals and mechanisms affecting the expression and activity of the isoforms of the p53 family in gastric cancer. Activators are indicated in red and repressors in blue. Underlines indicate existing clinically relevant data.

Figure 5

Therapeutic strategies targeting the p53 family that have been investigated in gastric cancer.