TP53 and its Regulatory Genes as Prognosis of Cutaneous Melanoma

Abstract

The present study was the first comprehensive investigation of genetic mutation and expression levels of the p53 signaling genes in cutaneous melanoma through various genetic databases providing large datasets. The mutational landscape of p53 and its signaling genes was higher than expected, with TP53 followed by CDKN2A being the most mutated gene in cutaneous melanoma. Furthermore, the expression analysis showed that TP53, MDM2, CDKN2A, and TP53BP1 were overexpressed, while MDM4 and CDKN2B were under-expressed in cutaneous melanoma. Overall, TCGA data revealed that among all the other p53 signaling proteins, CDKN2A was significantly higher in both sun and non-sun-exposed healthy tissues than in melanoma. Likewise, MDM4 and TP53BP1 expressions were markedly greater in non-sun-exposed healthy tissues compared to other groups. However, CDKN2B expression was higher in the sun-exposed healthy tissues than in other tissues. In addition, various genes were expressed significantly differently among males and females. In addition, CDKN2A was highly expressed in the SK-MEL-30 skin cancer cell line, whereas, Immune cell type expression analysis revealed that the MDM4 was highly expressed in naïve B-cells. Furthermore, all six genes were significantly overexpressed in extraordinarily overweight or obese tumor tissues compared to healthy tissues. MDM2 expression and tumor stage were closely related. There were differences in gene expression across patient age groups and positive nodal status. TP53 showed a positive correlation with B cells, MDM2 with CD8+T cells, macrophages and neutrophils, and MDM4 with neutrophils. CDKN2A/B had a non-significant correlation with all six types of immune cells. However, TP53BP1 was positively correlated with all five types of immune cells except B cells. Only TP53, MDM2, and CDKN2A had a role in cutaneous melanoma-specific tumor immunity. All TP53 and its regulating genes may be predictive for prognosis. The results of the present study need to be validated through future screening, in vivo, and in vitro studies.

Keywords: Mutations; cutaneous melanoma; expression; p53 signaling genes.

Figure 1.

p53 signaling genes mutants identified in skin cancer/cutaneous melanoma. P53 signaling gene mutations in skin cancer patients were generally detected from COSMIC (A-F) and skin cutaneous melanoma from cBio cancer genomics (G-J). (K) Oncoprint for skin cutaneous melanoma derived from cBioPortal.

Figure 2.

p53 signaling proteins mRNA expression in skin cutaneous melanoma and normal tissues in GEPIA. (A) mRNA expression profile, with red representing tumor tissue and green representing normal tissue. On the box plot, (B) mRNA expression. CDKN2A protein expression in skin cancer and normal tissues. *P = .05 and cutoff = 1.5 for |Log2 (fold-change)|. The level of mRNA expression was shown on a log scale.

Figure 3.

CDKN2A and MDM2 protein expression in melanoma and tumor-adjacent normal tissues. N: tumor-adjacent normal tissues; T: tumor tissues.

Figure 4.

p53 signaling proteins mRNA expression in the sun and non-sun exposed normal tissues in TCGA: (A) mRNA expression in general for both male and female, (B) mRNA expression for TP53 in male versus female, (C) mRNA expression for MDM2 in male versus female, (D) mRNA expression for MDM4 in male versus female, (E) mRNA expression for CDKN2A in male versus female, (F) mRNA expression for CDKN2B in male versus female, and (G) mRNA expression for TP53BP1 in male versus female. ANOVA calculated P values with recommended option Tukey’s multiple comparison test. Error bars indicate S.E.M. *P = .05.

Figure 5.

P53 signaling proteins expression in Skin cancer cell lines and immune cell-type expression: (A) expression in skin cancer cell lines (TCGA) and (B) immune cell type expression (Monaco dataset). The Monaco dataset contains data for immune cell types healthy donors’ peripheral blood mononuclear cell (PBMC) fraction using RNA-seq and flow cytometry.

Figure 6.

Top 5 Significant GO enrichment analysis in cellular component terms, biological process terms, and molecular function terms of different expressed p53 signaling genes.