PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines

Abstract

Deletions detected in cytogenetic and loss of heterozygosity (LOH) studies indicate that at least one tumour suppressor gene maps to the long arm of chromosome 10. Previous deletion mapping studies have observed LOH on 10q in about 30% of melanomas analysed. The PTEN gene, mapping to chromosome band 10q23.3, encodes a protein with both lipid and protein phosphatase activity. Somatic mutations and deletions in have been detected in a variety of cell lines and tumours, including melanoma samples. We performed mutation analyses and extensive allelic loss studies to investigate the role this gene plays in melanoma pathogenesis. We found that a total of 34 out of 57 (60%) melanoma cell lines carried hemizygous deletions of chromosome 10q encompassing the PTEN locus. A further three cell lines carried smaller deletions excluding PTEN. Inactivation of both PTEN alleles by exon-specific homozygous deletion or mutation was observed in 13 out of 57 (23%) melanoma cell lines. The mutation spectrum observed does not indicate an important role for ultraviolet radiation in the genesis of these mutations, and evidence from three cell lines supports the acquisition of PTEN aberrations in culture. Ten out of 49 (20%) matched melanoma tumour/normal samples harboured hemizygous deletions of either the whole chromosome or most of the long arm. Mutations within were detected in only one of the 10 tumours demonstrating LOH at 10q23 that were analysed. These results suggest that PTEN inactivation may be important for the propagation of melanoma cells in culture, and that another chromosome 10 tumour suppressor gene may be important for melanoma pathogenesis.

Modeling Genomic Diversity and Tumor Dependency in Malignant Melanoma

“…S3A). However, consistent with prior DNA sequencing analyses of short-term melanoma cultures and primary tumors (40,41), only 8 of 78 lines examined by sequencing contained inactivating PTEN mutations; of these samples, only 5 also harbored hemizygous loss and LOH of chromosome 10. Using sample-matched gene expression data, we then examined PTEN mRNA expression in relation to genomic deletion.…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…PTEN regulates PIP 3 levels, and its inactivation results in accumulation of PIP 3 , AKT hyperphosphorylation, and enhanced cell survival/ proliferation. In melanoma, allelic loss or altered expression of PTEN comprises 20% and 40% of melanoma tumors, respectively (Pollock et al 2002;Mikhail et al 2005;Slipicevic et al 2005;Goel et al 2006), although somatic point mutations and homozygous deletions are rarely observed. Functionally, ectopic expression of PTEN in PTEN-deficient melanoma cells can abolish phospho-AKT activity, induce apoptosis, and suppress growth, tumorigenicity, and metastasis (Robertson et al 1998;Stewart et al 2002;Stahl et al 2003; for review, see Robertson 2005).…”

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

“…Homozygous CDKN2A deletions were identified in 27/47 cell lines emphasizing their importance in melanoma cells and in vitro establishment. Although frequent in cultured cells, PTEN homozygous deletions or somatic mutations are less common in primary melanomas, suggesting that this is a late genetic event or that epigenetic mechanisms are responsible for PTEN silencing in primary tumors (Pollock et al, 2002). Moreover, PTEN is likely not the only target gene on chromosome 10.…”