A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer

Liloglou, Triantafillos; Walters, Matthew S.; Maloney, Paul; Youngson, Judith; Field, John K.

doi:10.1016/s0169-5002(02)00078-8

Cited by 22 publications

(13 citation statements)

References 14 publications

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“…Variation in GSTM4 is not well studied with respect to disease outcomes. One study did find that a C-T polymorphism in intron 6 of GSTM4 conferred an increased risk for lung cancer (49). However, we observed no association for this SNP (rs650985) in our data nor did it drive the observed haplotype association.…”

Section: Discussioncontrasting

confidence: 95%

Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

Breton¹,

Vora²,

Salam³

et al. 2009

Am J Respir Crit Care Med

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Rationale: The glutathione S-transferases (GSTs) are important detoxification enzymes. Objectives: To investigate effects of variants in GST mu genes on lung function and assess their interactions with tobacco smoke exposure. Methods: In this prospective study, 14,836 lung function measurements were collected from 2,108 children who participated in two Southern California cohorts. For each child, tagging single nucleotide polymorphisms in GSTM2, GSTM3, GSTM4, and GSTM5 loci were genotyped. Using principal components and haplotype analyses, the significance of each locus in relation to level and growth of FEV 1 , maximum midexpiratory flow rate (MMEF), and FVC was evaluated. Interactions between loci and tobacco smoke on lung function were also investigated. Measurements and Main Results: Variation in the GST mu family locus was associated with lower FEV 1 (P 5 0.01) and MMEF (0.04). Two haplotypes of GSTM2 were associated with FEV 1 and MMEF, with effect estimates in opposite directions. One haplotype in GSTM3 showed a decrease in growth for MMEF (2164.9 ml/s) compared with individuals with other haplotypes. One haplotype in GSTM4 showed significantly decreased growth in FEV 1 (251.3 ml), MMEF (269.1 ml/s), and FVC (244.4 ml), compared with all other haplotypes. These results were consistent across two independent cohorts. Variation in GSTM2 was particularly important for FVC and FEV 1 among children whose mothers smoked during pregnancy. Conclusions: Genetic variation across the GST mu locus is associated with 8-year lung function growth. Children of mothers who smoked during pregnancy and had variation in GSTM2 had lower lung function growth.

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Section: Discussioncontrasting

confidence: 95%

Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

Breton¹,

Vora²,

Salam³

et al. 2009

Am J Respir Crit Care Med

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“…The role played by this enzyme in cancer remains obscure, but a recent study suggested an association between GST M4 polymorphisms and lung cancer risk, implying that the activity of this enzyme might be involved in tumour development [23]. GSH peroxidase 2 mRNA was also found to be more frequently expressed in tumour as compared to normal breast tissue; this enzyme can protect cells from free radicals and also regulate proliferation and apoptosis through redox signalling [24] and thus its increased expression may confer a survival advantage to tumour cells.…”

Section: Discussionmentioning

confidence: 99%

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Martínez

Kennedy

Doolan

et al. 2007

Breast Cancer Res Treat

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The complex role of drug metabolism-related enzymes and their possible influence in cancer development, treatment and outcome has not yet been completely elucidated. There is evidence that these enzymes can activate certain environmental procarcinogens to more toxic derivatives and thus a role has been proposed for them in carcinogenesis. The fact that they can also inactivate a number of chemotherapeutic drugs has raised the possibility of these enzymes influencing the sensitivity of tumour cells to anticancer agents. In this report, we analyse the expression of drug metabolism-related genes within a whole genome microarray study of 104 breast cancer and 17 normal breast specimens. Kaplan-Meier survival curves, Chi-squared, and Cox Regression analyses were used to identify associations between expression of gene transcripts and patients' clinicopathological and survival data. Our results show that several of these genes are significantly expressed in both normal and tumour tissue; in many cases, expression is altered in the tumour specimens as compared to normal breast tissue. Moreover, expression of ARNT2 and GST A1 was correlated with prognosis. Kaplan-Meier analysis showed expression of ARNT2 mRNA to correlate significantly with favourable disease outcome for patients, in terms of both their disease-free survival (P = 0.0094) and overall survival (P = 0.0018) times from diagnosis, while detection of GST A1 mRNA correlated with shortened disease-free survival (P = 0.0131) and overall survival (P = 0.0028). Multivariate analysis indicated GST A1 expression to be an independent prognostic factor for overall survival (P = 0.045). Our results suggest a possible use of ARNT2 and GST A1 as prognostic breast cancer biomarkers.

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“…This polymorphism can change an individual's susceptibility to disease and responsiveness to therapeutic drugs. For instance, a T2517C polymorphism in GSTM4 was shown to associate with an increased risk of developing lung cancer (Liloglou et al, 2002). The mechanistic basis for this association is currently unknown.…”

Section: Formationmentioning

confidence: 99%

GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance

et al. 2009

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Ewing's sarcoma is a malignant bone-associated tumor of children and young adults. Most cases of Ewing's sarcoma express the EWS/FLI fusion protein. EWS/FLI functions as an aberrant ETS-type transcription factor and serves as the master regulator of Ewing's sarcoma-transformed phenotype. We recently showed that EWS/FLI regulates one of its key targets, NR0B1, through a GGAAmicrosatellite in its promoter. Whether other critical EWS/FLI targets are also regulated by GGAA-microsatellites was unknown. In this study, we combined transcriptional analysis, whole genome localization data, and RNA interference knockdown to identify glutathione S-transferase M4 (GSTM4) as a critical EWS/FLI target gene in Ewing's sarcoma. We found that EWS/FLI directly binds the GSTM4 promoter, and regulates GSTM4 expression through a GGAA-microsatellite in its promoter. Reduction of GSTM4 levels caused a loss of oncogenic transformation. Furthermore, reduction of GSTM4 resulted in an increased sensitivity of Ewing's sarcoma cells to chemotherapeutic agents, suggesting a role for this protein in drug resistance. Consistent with this hypothesis, patients with Ewing's sarcoma whose tumors had higher levels of GSTM4 expression had worse outcomes than those with lower expression levels. These data show that GSTM4 contributes to the cancerous behavior of Ewing's sarcoma and define a wider role for GGAA-microsatellites in EWS/FLI function than previously appreciated. These data also suggest a novel therapeutic resistance mechanism, in which the central oncogenic abnormality directly regulates a resistance gene.

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A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer

Cited by 22 publications

References 14 publications

Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance

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