Epithelial ovarian cancer: influence of polymorphism at the glutathione S-transferase GSTM1 and GSTT1 loci on p53 expression

Abstract

Summary The importance of polymorphism in the glutathione S-transferase GSTM1, GSTT1 and, cytochrome P450, CYP2D6 loci in the pathogenesis of epithelial ovarian cancer has been assessed in two studies; firstly, a case-control study designed to determine the influence of these genes on susceptibility to this cancer, and secondly, the putative role of these genes in the protection of host cell DNA has been studied by comparing p53 expression in patients with different GSTM1, GSTT1 and CYP2D6 genotypes. The frequencies of GSTM1, GSTT1 and CYP2D6 genotypes in 84 cases and 325 controls were not different. Immunohistochemistry was used to detect p53 expression in 63 of these tumours. Expression was found in 23 tumours. Of the patients demonstrating immunopositivity, 20 (87%) were GSTM1 null. The frequency distributions of GSTM1 genotypes in p53-positive and -negative samples were significantly different (P= 0.002) and those for GSTT1 genotypes approached significance (exact P=0.057). The proportion of patients with both GSTM1 null and GSTT1 null was also significantly greater in the immunopositive (4/22) than in the immunonegative group (1/40) (P=0.0493). Single-strand conformational polymorphism (SSCP) analysis was used to detect mutations in the 23 tumour samples demonstrating p53 positivity. A shift in electrophoretic mobility of amplified fragments was found in 11 patients (exons 5, 6, 7 and 8) and these exons were sequenced. In eight samples a mutation was found. No SCCP variants were identified in the other 12 immunopositive patients. Sequencing of exons 4-9 of p53 from these tumours resulted in the detection of mutations in two patients (exons 5 and 7). Thus, in 23 patients who demonstrated immunopositivity, p53 mutations were found in nine patients with GSTM1 null (90.0%). In the 13 patients in whom no mutations were identified, 11 were GSTM1 null (84.6%). The data show that overexpression of p53 is associated with the GSTM1 null genotype. We propose the data are compatible with the view that GSTM1 and GSTT1 are critical in the detoxification of the products of oxidative stress produced during the repair of the ovarian epithelium. Thus, failure to detoxify products of this stress may result in damage to various genes in the host cell, including to p53, resulting in persistent expression of mutant protein. In other patients, oxidative stress effects damage to various genes, but not including p53, resulting in overexpression of wild-type p53.

Geographical Variations in TP53 Mutational Spectrum in Ovarian Carcinomas

“…Within Europe, the data from the following countries/regions were available: Poland, Germany (Kappes et al 1995;Meinhold-Heerlein et al 2001), Norway (Skomedal et al 1997;Smith-Sorensen et al 1998;Wang et al 2004aWang et al , 2004b, the United Kingdom (Jacobs et at. 1992;Milner et al 1993;Foulkes et al 1995;Sarhanis et al 1996;Tavassoli et al 1996;Fallows et al 2001), and France and Italy (Mazars et al 1991;Righetti et al 1996;Lavarino et al 2000). The last group was combined from two countries because of the low number of mutations published from each of these countries, and existence of reports that evaluated data from these two countries together.…”

Glutathione S-transferase polymorphisms and risk of ovarian cancer: A HuGE review

“…This study is limited by the use of volunteer controls and by the small sample size. Associations with GSTM1a and GSTM1b genotype were examined by Sarhanis et al 52 in a study involving 84 patients with epithelial ovarian cancer and 312 control patients from the same hospital in North Staffordshire. No associations were observed with the null GSTM1 genotype in comparisons with homozygosity for either the GSTM1a or GSTM1b genotypes ( Table 2).…”

Biomarcadores de suscetibilidade à endometriose

“…Além disto, observaram que o genótipo nulo para GSTM1 foi significativamente elevado no grupo das pacientes com câncer ovariano em relação ao controle (59,0 vs 48,9%) e sugeriram que focos endometrióticos em mulheres com este genótipo podem apresentar transformação maligna devido à ineficiência no controle do estresse oxidativo. Já é conhecido o fato de que o gene GSTM1 pode desempenhar papel crítico na detoxificação de produtos do estresse oxidativo produzidos durante o reparo do epitélio ovariano 19 . Uma vez que a expressão do gene CYP1A1 parece ser regulada na transcrição por fatores resultantes do estresse oxidativo 20 ; sua elevada atividade pode também ser deletéria e contribuir para a suscetibilidade a algumas, doenças; incluindose a endometriose.…”