Haplotype-Environment Interactions That Regulate the Human Glutathione <i>S</i>-Transferase P1 Promoter

Cauchi, Stéphane; Han, Weiguo; Kumar, Shalini; Spivack, Simon D.

doi:10.1158/0008-5472.can-05-4457

Cited by 19 publications

(24 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we report 33 possible haplotypes for the GSTP1 promoter and 14 of these were found in tumor DNA from breast cancer patients. In a recent report, 10 polymorphisms in the GSTP1 promoter were assembled into haplotypes whereby the two most frequent haplotypes were reported with similar frequencies to those here (31). Interestingly, Cauchi and colleagues (31) reported differential inducibility of the different GSTP1 haplotypes by exposure to environmental agents and recommended further studies to assess the functionality of these haplotypes.…”

Section: Cancer Researchsupporting

confidence: 58%

GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas

et al. 2008

View full text Add to dashboard Cite

The CpG island spanning the transcription start of the glutathione S-transferase P1 becomes methylated in a variety of human cancers including breast cancer. To study the effect of sequence variation on hypermethylation of the GSTP1 promoter, we analyzed the genetic and epigenetic variability in 90 tumors from patients with locally advanced breast cancer. High-resolution quantitative analysis revealed large variability in the DNA methylation levels. Lack of methylation was more often observed in the basal and normal-like estrogen receptor (ER)-negative tumors, and methylated GSTP1 was associated with better overall survival (P = 0.00063). Studies of the genetic variation identified 14 different haplotypes. The distribution of methylation levels of tumors homozygous for the most frequent haplotype was significantly different from other haplotype combinations (P = 0.011), the difference being more pronounced in ER-positive (P = 0.005) and progesterone receptor-positive (P = 0.008) tumors. Regression modeling identified the ER status and haplotype as the main determinants of DNA methylation variability. We identified a putative c-Myb response element (MRE) that was present in one of two minimal promoter haplotypes. In vitro analysis showed that c-Myb binds to the MRE, but binding was weakened by the two polymorphisms. Transient cotransfections in luminal-type and basal-like breast cancer cell lines confirmed cell-specific differential binding of c-Myb to the polymorphic sites, leading to a change in the expression from the GSTP1 promoter in vivo. GSTP1 expression was moderately but significantly (P = 0.01) reduced after siRNA-mediated knockdown of c-Myb. Our results indicate that haplotype structure of a promoter is important for the extent of DNA methylation. [Cancer Res 2008;68(14):5562-71]

show abstract

Section: Cancer Researchsupporting

confidence: 58%

GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The variant “A” allele of SNP1 corresponds to a haplotype of the promoter region that is associated with reduced GSTP1 activity28 and thus the association with increased risk of asthma is biologically plausible. The observed association is consistent with our earlier observation of associations between SNP1 and early and late onset asthma 23…”

Section: Discussionmentioning

confidence: 99%

“…The functional model included Ile105Val and rs6591255 based on their functional effects 12 13 28. We selected the best model based on the likelihood ratio tests (comparing “base” (without any genetic information) and “full” models (genetic information added to the base model)).…”

Section: Methodsmentioning

confidence: 99%

Glutathione-S-transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children

Islam

Berhane

McConnell

et al. 2009

Thorax

121

View full text Add to dashboard Cite

Background: Because asthma has been associated with exercise and ozone exposure, an association likely mediated by oxidative stress, we hypothesised that glutathione-S-transferase (GST)P1, GSTM1, exercise and ozone exposure have interrelated effects on the pathogenesis of asthma. Methods: Associations of the well characterised null variant of GSTM1 and four single nucleotide polymorphisms (SNPs) that characterised common variation in the GSTP1 locus with new onset asthma in a cohort of 1610 school children were examined. Children's exercise and ozone exposure were classified using participation in team sports and community annual average ozone levels, respectively. Results: A two SNP model involving putatively functional variants (rs6591255, rs1695 (Ile105Va)) best captured the association between GSTP1 and asthma. The risk of asthma was lower for those with the Val allele of Ile105Val (hazard ratio (HR) 0.60, 95% CI 0.4 to 0.8) and higher for the variant allele of rs6591255 (HR 1.40, 95% CI 1.1 to 1.9). The risk of asthma increased with level of exercise among ile 105 homozygotes but not among those with at least one val 105 allele (interaction p value = 0.02). The risk was highest among ile 105 homozygotes who participated in >3 sports in the high ozone communities (HR 6.15, 95% CI 2.2 to 7.4). GSTM1 null was independently associated with an increased risk of asthma and showed little variation with air pollution or GSTP1 genotype. These results were consistent in two independent fourth grade cohorts recruited in 1993 and 1996. Conclusion: Children who inherit a val 105 variant allele may be protected from the increased risk of asthma associated with exercise, especially in high ozone communities. GSTM1 null genotype was associated with an increased risk of asthma.

show abstract

“…Gene expression of GSTP1 in alveoli, alveolar macrophages, and respiratory bronchioles is more abundant than that of GSTM and other GSTs (21, 44). It is therefore possible that GSTP1 may play an important role in local detoxification of xenobiotics in the lung, but is mostly non-inducible to tobacco exposure, which we have observed in multiple in vitro studies (28, 45, 46). If true, this is biologically problematic, as this phase I versus phase II imbalance potentially favors mutagenesis, rather than mutagen quenching.…”

Section: Discussionmentioning

confidence: 90%

Smoking-Related Gene Expression in Laser Capture–Microdissected Human Lung

Tan

Wang

Xiong

et al. 2009

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose Inter-individual differences in quantitative expression could underlie a propensity for lung cancer. To determine precise individual gene expression signatures on a lung compartment-specific basis, we investigated the expression of carcinogen metabolism genes encoding cytochromes P450 (CYP) 1B1, 2A13, glutathione S-transferase (GST) P1, and a tumor suppressor gene p16 in laser capture microdissected samples of human alveolar compartment (AC) and bronchial epithelial compartment (BEC) lung tissue from 62 smokers and non-smokers. Experimental Design Tobacco exposure was determined by plasma nicotine, cotinine, and smoking history. Precise mRNA expression was determined using our RNA-specific qRT-PCR strategy, and correlated with detailed demographic and clinical characteristics. Results Several correlations of mRNA expression included: (a) CYP1B1 in AC (positively with plasma nicotine level, P = 0.008; plasma cotinine level, P = 0.001); (b) GSTP1 in AC (positively with plasma cotinine level, P = 0.003); (c) GSTP1 in BEC (negatively with smoke dose, P = 0.043; occupational risk, P = 0.019). CYP2A13 was rarely expressed in AC, and not expressed in BEC. p16 expression was not correlated with any measured factor. For each gene, subjects showed expression that was individually concordant between these compartments. No clear association of mRNA expression with lung cancer risk was observed in this pilot analysis. Conclusions The association between lung mRNA expression and tobacco exposure implies that gene-tobacco interaction is a measurable quantitative trait, albeit with wide inter-individual variation. Gene expression tends to be concordant for alveolar and bronchial compartments for these genes in an individual, controlling for proximate tobacco exposure.

show abstract

Haplotype-Environment Interactions That Regulate the Human Glutathione S-Transferase P1 Promoter

Cited by 19 publications

References 48 publications

GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas

GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas

Glutathione-S-transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children

Smoking-Related Gene Expression in Laser Capture–Microdissected Human Lung

Contact Info

Product

Resources

About