Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines.
Both inactivation of the tumor suppressor gene, PTEN/MMAC1, and oncogenic activation of RAS have been described in human cutaneous melanoma. In mice, activation of a RAS-containing pathway is a necessary step in the pathogenesis of murine melanomas. Because PTEN negatively regulates on the downstream effects of phosphatidylinositol-3-kinase (PI3-K), we hypothesized that the loss of PTEN/MMAC1 and the activation of RAS may be largely equivalent because RAS is a known positive upstream regulator of PI3-K. We expanded our previous survey of PTEN/MMAC1 mutations and analyzed the RAS status of 53 cutaneous melanoma cell lines, 18 glioma cell lines, and 17 uncultured cutaneous melanoma metastasis. Overall, 51% of the cell lines had alterations in either PTEN/MMAC1 or RAS. We found 16 cell lines (30%) with alterations in PTEN/MMAC1 and 11 cell lines (21%) with activating NRAS mutations; only 1 cell line had concurrent alterations in both genes. Moreover, glioma cell lines with a high frequency of PTEN/MMAC1 inactivation had no identifiable RAS alterations. Ectopic expression of PTEN in several cutaneous melanoma cell lines suppressed colony formation irrespective of PTEN/MMAC1 status; furthermore, PTEN expression in cell lines carrying activated RAS also suppressed colony formation. The relative reciprocity of PTEN/MMAC1 abrogation and NRAS activation suggests that the two genetic changes, in a subset of cutaneous melanomas, are functionally overlapping.
Tsao
H
H
Department of Dermatology, Massachusetts General Hospital and Dana-Farber/Partners CancerCare, Boston 02114, USA.
Zhang
X
X
Fowlkes
K
K
Haluska
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FG
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics; D005091:Exons; D016368:Frameshift Mutation; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D005910:Glioma / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008546:Melanoma, Experimental / Q000235:genetics; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017354:Point Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017384:Sequence Deletion; D012878:Skin Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)