Glutathione S-Transferase GSTM1, GSTT1 and p53 Codon 72 Polymorphisms in Human Tumor Cells

Abstract

The genes of the glutathione S-transferase (GST) family encode enzymes that appear to be critical in cellular protection against the cytotoxic effects, whereas p53 is a tumor suppressor gene. Despite a large number of studies on germline polymorphisms of GSTM1, GSTT1 and p53 genes, there have been very few reports on genotyping of these genes in human malignant tumor cells. In this study, we investigated GSTM1, GSTT1 and p53 codon 72 polymorphisms in a variety of human tumor cell lines originating from different organs to clarify tissue-specific polymorphic frequency of these genes in human solid tumors. The GSTM1 and GSTT1 genetic polymorphisms were evaluated using multiplex PCR techniques and PCR-RFLP analysis was conducted to identify p53 codon 72 genotypes. Gene expression of GSTM1 or GSTT1 was detected by RT-PCR in the cells with respective present genotype for each. Polymorphisms of p53 codon 72 detected by PCR-RFLP were also confirmed using SSCP and sequence analyses. GSTM1 and GSTT1 genotypes were various in 104 cell lines examined. Null GSTM1 genotype was dominant in small cell lung, kidney and ovarian carcinoma cells, whereas null GSTT1 genotype was dominant in cervical and endometrial carcinoma cells. GSTM1 and GSTT1 genotypes in ovarian carcinoma cells were quite similar to those in small cell lung carcinoma cells. Polymorphic frequency of p53 codon 72 was also various among the cells, however, the Pro allele was found in only 1 of 6 kidney, 14 cervical and 4 endometrial carcinoma cell lines. There was a significant difference in GSTM1 and p53 genotypes between 34 small cell and 24 non small cell lung carcinoma cells (P < 0.01). Combined study on the distribution of GSTM1, GSTT1 and p53 genotypes revealed that null GSTM1 genotype was associated with the Arg allele of p53 codon 72 in 58 lung carcinoma cells and null GSTT1 genotype was associated with the Pro/Pro homozygote in 104 tumor cell lines examined. This is the first study examining GSTM1, GSTT1 and p53 codon 72 polymorphisms in a variety of human solid tumor cells and suggesting that polymorphic frequency of these genes may be tissue- and organ-specific. The molecular interaction between GST gene defects and p53 codon 72 genotype in the development of human malignant tumors should be further investigated.

Genetic polymorphisms of glutathione S transferase and cervical intraepithelial neoplasia

“…The genes for both GSTM1 and GSTT1 isoforms could exhibit an insertion/deletion polymorphism null alleles/ genotypes resulting in loss of enzymatic activity which was associated with a number of malignancies including cervical neoplasia (12)(13)(14). Previous reports have associated GST M1 and T1 null genotype with an enhanced risk of precancerous lesions or cervical cancer (15,16), but still, other studies have not confirmed this correlation (12). Considering that null alleles of GSTM1 and GSTT1 genes could be used as potential molecular markers in cervical cancer prevention, further large studies and adequate meta-analyses are needed to confirm and validate this hypothesis.…”

“…The glutathione S-transferases (GSTs) represent an important class of detoxifying enzymes belonging to phase II detoxification enzymes superfamily, which protect cells against endogenous and exogenous molecular injury inducing compounds including mutagens, carcinogens and other toxic chemicals, thus playing a crucial role in the detoxification process (11). The genes for both GSTM1 and GSTT1 isoforms could exhibit an insertion/deletion polymorphism null alleles/ genotypes resulting in loss of enzymatic activity which was associated with a number of malignancies including cervical neoplasia (12)(13)(14).…”

Potential impact of (rs 4645878) BAX promoter −248G>A and (rs 1042522) TP53 72Arg>pro polymorphisms on epithelial ovarian cancer patients

“…The role of genetic factors in development of ovarian cancer has not been explored. According to earlier studies, genetic polymorphism in cell cycle regulatory and pro-apoptotic genes leads to cancer development [7,8]. Prevalence of BRCA mutation in sporadic ovarian cancer has been found very less and no change has been found in p53 mutation frequencies between BRCA-associated and sporadic ovarian cancer [9,10].…”

Sistema Glutation-S-Transferase como fator prognóstico no carcinoma papilífero da tireoide

“…Os compostos eletrofílicos, tanto endógenos como exógenos, estão constantemente em contato com nossas células e são agentes potencialmente mutagênicos por reagirem sobre a cadeia de DNA provocando modificação de sua estrutura. As enzimas do Glutation-S-Transferase têm um importante papel na carcinogênese dos tumores humanos porque estão envolvidas na neutralização e detoxificação de uma variedade desses compostos, tanto derivados do próprio metabolismo celular, como de substâncias produzidas por indústrias químicas, incluindo metileno clorídrico, etileno, brometo de etídeo, óxido etileno, e 1,3-butadieno [5][6][7][8] . Atualmente seis classes de GST's são conhecidas: alpha, mu, pi, theta, omega e zeta 1 .…”

“…Na glândula tireoide esse risco aumenta em 2,6 vezes 1,5,6,8,12,13 . Sendo o GST um fator de proteção do DNA da célula, os pacientes com genótipo nulo para esse sistema não possuem essa proteção e, consequentemente, estão mais propensos ao desenvolvimento de diversos tumores [5][6][7][8][12][13][14][15][16][17][18][19] . As células cancerosas possuem habilidade de superexpressar determinados genes a fim de adquirir qualidades que permitam sua multiplicação descontrolada.…”