Phenotype of glutathione S-transferase Mu (GSTM1) and susceptibility to malignant melanoma

Abstract

Summary The isoenzyme Mu of glutathione S-transferase (GSTM 1) is dominantly inherited, and the prevalence of this isoenzyme in the population is about 60%. The (Longstreth et al., 1992). As a host genetic factor, dysplastic naevi (DN), which are relatively distinct melanocytic lesions, can be precursors of melanoma, and responsible for the tendency of melanoma to run in families. Metabolic factors such as the isoenzyme Mu of glutathione S-transferase (GSTM1) should also be considered. GSTM1 has polymorphic expression, and about half the population from various racial groups lack it (Hussey et al., 1986). The enzyme detoxifies various carcinogenic electrophiles including epoxides, and it has therefore been attributed a protective role against neoplasias associated with smoking. Indeed, a major susceptibility to lung (Seidegard et al., 1986), bladder and larynx cancer (Lafuente et al., 1993) has been shown among smokers lacking GSTM1.When ROS damage DNA, the derived residues, which are cytotoxic and cytostatic, are also substrates of GSTM1, suggesting that these isoforms also have a role in the DNA repair system (Ketterer and Meyer, 1989).We therefore designed a study to determine whether GSTM 1 deficiency may confer susceptibility to malignant melanoma (MM) on the basis of the antioxidant properties of this isoenzyme against UV-derived ROS. Materials and methodsA total of 197 white melanoma patients were recruited at the Dermatology Department at the Hospital Clinic of Barcelona in 1993. Ninety-three patients were men (mean age 53.0 ± 19.0) and 104 were women (mean age 51.06 ± 16.4).

Genetics of melanoma predisposition

“…Initial studies comparing melanoma cases with controls in the predominantly Anglo-Celtic populations of the United Kingdom and Australia found the same frequency (52%) of GSTM1 nullizygotes in both groups (Heagerty et al, 1994;Shanley et al, 1995) (Table 5). In contrast, there was a significantly increased frequency of GSTM1 null phenotype in melanoma cases compared with controls (58 versus 41%, P ¼ 0.002) from a Hospital-based study in Barcelona (Lafuente et al, 1995). The most noticeable feature of this study was the much lower frequency of nullizygotes in the Spanish controls compared to that observed in other Caucasian control populations.…”

EGF +61 gene polymorphism and susceptibility to and prognostic markers in cutaneous malignant melanoma

“…1 Relatively little is known of the genetic factors that mediate susceptibility to and prognosis in sporadic CMM, although polymorphisms associated with the MCR1, 2,3 CDKN2A, 4 XRCC3 (DNA repair), 5 GSTM1, 6 vitamin D receptor, 7 cytochrome P-450 CYP2D6, 8 HLA-DQB1, 9,10 IL-10 11 and VEGF 12 genes may play some role in susceptibility to and/or prognosis in CMM. Accordingly, one report, 13 demonstrating a highly significant association between a functional SNP in the EGF gene (chromosome 4q25-q27) and both susceptibility to and invasive tumour Breslow thickness (as a marker of disease prognosis), is of note.…”

Chemoresistance of Human Malignant Melanoma: Cellular and Molecular Aspects

“…The elevated expression of cytosolic GST in melanocytes is supposed to be engaged in detoxification of hazardous by-pro-ducts from melanin synthesis [32]. In line with this argumentation, humans with an inherent deficiency for GST expression are at higher risk to develop MM [33]. Regarding MM, several studies reported a high expression of the GST and a lower or lacking one of the isoforms ␣ and in tumor tissue as well as cell lines [34,35].…”