GLUTATHIONE TRANSFERASE P1-1 EXPRESSION IN HUMAN-MELANOMA METASTASES - CORRELATION TO N-RAS MUTATIONS AND EXPRESSION

Expression of the detoxication enzyme glutathione transferase P1-1 (GST P1-1) at elevated levels has been noted in many types of human tumors, including melanomas, The products of the human II-PAS, K-PAS and N-RAS genes play a key role in intracellular signal transduction leading to transcriptional activation of AP-1 (Fos/Jun) responsive genes, The oncogenic mutated forms of the ras proteins are constitutively active and interfere with normal signal transduction, Mutated PAS genes as well as increased expression of wild-type ras proteins are common features in human tumors including melanoma, We have characterized 30 melanoma metastases from 23 melanoma patients with reference to N-RAS expression and mutation as well as to GST P1 expression (immunohistochemistry and genetic analysis). Twenty-three of 30 samples (70%) had high N-Ras p21 and/or N-RAS codon 61 mutations and 18 of these 23 samples also had high GST P1-1 immunoreactivity, Seven of 30 (23%) samples had low N-Ras p21 immunoreactivity and no detectable N-RAS codon 61 mutations, Six of these 7 samples (86%) also had low GST P1-1 immunoreactivity. The results indicate a statistically significant correlation (Spearman correlation coefficient, r = 0.56, p = 0.001, 2-tailed test) and provide, for the first time, indirect evidence for a possible coregulation of N-RAS and GST PI in human malignant melanoma which should be further evaluated.