Genetic alterations of PTEN in human melanoma

Abstract

The PTEN gene is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Inactivating mutations and deletions of the PTEN gene are found in many types of cancers, including melanoma. However, the exact frequency of PTEN alteration in melanoma is unknown. In this study, we comprehensively reviewed 16 studies on PTEN genetic changes in melanoma cell lines and tumor biopsies. To date, 76 PTEN alterations have been reported in melanoma cell lines and 38 PTEN alterations in melanoma biopsies. The rate of PTEN alterations in melanoma cell lines, primary melanoma, and metastatic melanoma is 27.6, 7.3, and 15.2%, respectively. Three mutations were found in both melanoma cell lines and biopsies. These mutations are scattered throughout the gene, with the exception of exon 9. A mutational hot spot is found in exon 5, which encodes the phosphatase activity domain. Evidence is also presented to suggest that numerous homozygous deletions and missense variants exist in the PTEN transcript. Studying PTEN functions and implications of its mutations and other genes could provide insights into the precise nature of PTEN function in melanoma and additional targets for new therapeutic approaches.

Fig. 1

Schematic representation of PTEN gene and genetic alterations identified in melanoma. a Structural representation of PTEN with 9 exons represented by boxes. The exon 5 represents the hot spot of mutations and the different numbers show the mutated codons. The vertical lines correspond to the localization of PTEN mutations in the exons and the height of the lines indicates the mutation frequencies. The horizontal lines refer to different extent of deletions. b Schematic representation of PTEN protein and its biological functions. PTEN contains two key domains: the phosphatase domain (in red; amino acids 14–185), which possesses lipid and protein phosphatase activities; and the C2 domain (in grey; amino acids 190–350), which is responsible for lipid binding and membrane localization. There are two other important domains; the carboxy-terminal region (amino acids 351–400), which is involved in cell migration and regulation of protein stability; and the PDZ-binding domain (in yellow; amino acids 401–403), which is important for protein–protein interactions