GSTP1 rs1138272 Polymorphism Affects Prostate Cancer Risk

Background and Objectives: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (GSTP1). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of GSTP1*Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including GSTP1*IIe105Val rs1695 or GSTM1 and GSTT1 deletion polymorphisms. Materials and Methods: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. Results: We found that carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89–8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19–2.73, p = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with GSTP1*C haplotype, represented by both variant alleles (GSTP1*Val rs1695 + GSTP1*Val rs1138272), had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56–11.65, p < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (GSTM1*active, GSTT1*null, GSTP1*Val rs1695 and GSTP1*Val rs1138272) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55–8.61, p = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05–44.93, p < 0.001). Conclusion: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially GSTP1, highlighting the role of gene–gene interactions in human susceptibility to this cancer.

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Polymorphisms in Genes Encoding Glutathione Transferase Pi and Glutathione Transferase Omega Influence Prostate Cancer Risk and Prognosis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.620690 ◽

2021 ◽

Vol 8 ◽

Author(s):

Veljko Santric ◽

Dejan Dragicevic ◽

Marija Matic ◽

Milica Djokic ◽

Marija Pljesa-Ercegovac ◽

...

Keyword(s):

Prostate Cancer ◽

Glutathione Transferase ◽

Redox Homeostasis ◽

Prostate Cancer Risk ◽

Gst Polymorphisms ◽

Increased Risk ◽

Genes Encoding ◽

Gst Polymorphism ◽

First Time

Considering the pleiotropic roles of glutathione transferase (GST) omega class members in redox homeostasis, we hypothesized that polymorphisms in GSTO1 and GSTO2 might contribute to prostate cancer (PC) development and progression. Therefore, we performed a comprehensive analysis of GSTO1 and GSTO2 SNPs’ role in susceptibility to PC, as well as whether they might serve as prognostic biomarkers independently or in conjunction with other common GST polymorphisms (GSTM1, GSTT1, and GSTP1). Genotyping was performed in 237 PC cases and 236 age-matched controls by multiplex PCR for deletion of GST polymorphisms and quantitative PCR for SNPs. The results of this study, for the first time, demonstrated that homozygous carriers of both GSTO1*A/A and GSTO2*G/G variant genotypes are at increased risk of PC. This was further confirmed by haplotype analysis, which showed that H2 comprising both GSTO1*A and GSTO2*G variant alleles represented a high-risk combination. However, the prognostic relevance of polymorphisms in GST omega genes was not found in our cohort of PC patients. Analysis of the role of other investigated GST polymorphisms (GSTM1, GSTT1, and GSTP1) in terms of PC prognosis has shown shorter survival in carriers of GSTP1*T/T (rs1138272) genotype than in those carrying at least one referent allele. In addition, the presence of GSTP1*T/T genotype independently predicted a four-fold higher risk of overall mortality among PC patients. This study demonstrated a significant prognostic role of GST polymorphism in PC.

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Assessing the Role of Copy Number Variants in Prostate Cancer Risk and Progression using a Novel Genome-Wide Screening Method

10.21236/ada568305 ◽

2012 ◽

Author(s):

Donna Lehman ◽

August Blackburn ◽

Robin Leach

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Copy Number ◽

Screening Method ◽

Copy Number Variants ◽

Prostate Cancer Risk ◽

Genome Wide

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CHEK2∗1100delC Mutation and Risk of Prostate Cancer

Prostate Cancer ◽

10.1155/2014/294575 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 24

Author(s):

Victoria Hale ◽

Maren Weischer ◽

Jong Y. Park

Keyword(s):

Prostate Cancer ◽

Current Knowledge ◽

Prostate Cancer Screening ◽

Critical Role ◽

Prostate Cancer Risk ◽

Conclusive Evidence ◽

Increased Risk ◽

History Of ◽

Cancer Studies

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer.CHEK2plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, ofCHEK2on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussedCHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating thatCHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.

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Associations Between Polymorphisms in Genes Related to Oxidative Stress and DNA Repair, Interactions With Serum Antioxidants, and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

Frontiers in Oncology ◽

10.3389/fonc.2021.808715 ◽

2022 ◽

Vol 11 ◽

Author(s):

Zhihong Gong ◽

Mary E. Platek ◽

Cathee Till ◽

Phyllis J. Goodman ◽

Catherine M. Tangen ◽

...

Keyword(s):

Oxidative Stress ◽

Prostate Cancer ◽

Dna Repair ◽

Cancer Prevention ◽

Prostate Cancer Risk ◽

Minor Allele ◽

Cancer Etiology ◽

Lower Serum ◽

Prostate Cancer Prevention

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

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Recent Advances in Molecular Diagnosis of Thyroid Cancer

Journal of Thyroid Research ◽

10.4061/2011/384213 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Ioannis Legakis ◽

Konstantinos Syrigos

Keyword(s):

Thyroid Cancer ◽

Tumor Development ◽

Disease Process ◽

Genetic Alterations ◽

Aberrant Methylation ◽

Novel Treatments ◽

Molecular Alterations ◽

Molecular Events ◽

Diagnosis Of Thyroid Cancer

Recent molecular studies have described a number of abnormalities associated with the progression and dedifferentiation of thyroid carcinoma. These distinct molecular events are often associated with specific stages of tumor development. In particular, remarkable advances have occurred in several major biological areas of thyroid cancer, including the molecular alterations for the loss of radioiodine avidity of thyroid cancer, the pathogenic role of the MAP kinase and PI3K/Akt pathways and their related genetic alterations, and the aberrant methylation of functionally important genes in thyroid tumorigenesis and pathogenesis. Recognition of these features is crucial to the management of patients with thyroid cancer. Novel treatments are being designed based on our enhanced understanding of this disease process.

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Combination of Peri-Tumoral and Intra-Tumoral Radiomic Features on Bi-Parametric MRI Accurately Stratifies Prostate Cancer Risk: A Multi-Site Study

Cancers ◽

10.3390/cancers12082200 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2200 ◽

Cited By ~ 1

Author(s):

Ahmad Algohary ◽

Rakesh Shiradkar ◽

Shivani Pahwa ◽

Andrei Purysko ◽

Sadhna Verma ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Risk Stratification ◽

Operating Characteristic ◽

Prostate Cancer Risk ◽

Magnetic Resonance Imaging Mri ◽

Validation Set ◽

And Diffusion ◽

Risk Categories

Background: Prostate cancer (PCa) influences its surrounding habitat, which tends to manifest as different phenotypic appearances on magnetic resonance imaging (MRI). This region surrounding the PCa lesion, or the peri-tumoral region, may encode useful information that can complement intra-tumoral information to enable better risk stratification. Purpose: To evaluate the role of peri-tumoral radiomic features on bi-parametric MRI (T2-weighted and Diffusion-weighted) to distinguish PCa risk categories as defined by D’Amico Risk Classification System. Materials and Methods: We studied a retrospective, HIPAA-compliant, 4-institution cohort of 231 PCa patients (n = 301 lesions) who underwent 3T multi-parametric MRI prior to biopsy. PCa regions of interest (ROIs) were delineated on MRI by experienced radiologists following which peri-tumoral ROIs were defined. Radiomic features were extracted within the intra- and peri-tumoral ROIs. Radiomic features differentiating low-risk from: (1) high-risk (L-vs.-H), and (2) (intermediate- and high-risk (L-vs.-I + H)) lesions were identified. Using a multi-institutional training cohort of 151 lesions (D1, N = 116 patients), machine learning classifiers were trained using peri- and intra-tumoral features individually and in combination. The remaining 150 lesions (D2, N = 115 patients) were used for independent hold-out validation and were evaluated using Receiver Operating Characteristic (ROC) analysis and compared with PI-RADS v2 scores. Results: Validation on D2 using peri-tumoral radiomics alone resulted in areas under the ROC curve (AUCs) of 0.84 and 0.73 for the L-vs.-H and L-vs.-I + H classifications, respectively. The best combination of intra- and peri-tumoral features resulted in AUCs of 0.87 and 0.75 for the L-vs.-H and L-vs.-I + H classifications, respectively. This combination improved the risk stratification results by 3–6% compared to intra-tumoral features alone. Our radiomics-based model resulted in a 53% accuracy in differentiating L-vs.-H compared to PI-RADS v2 (48%), on the validation set. Conclusion: Our findings suggest that peri-tumoral radiomic features derived from prostate bi-parametric MRI add independent predictive value to intra-tumoral radiomic features for PCa risk assessment.

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Hormonal Predictors of Prostate Cancer: A Meta-Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.4.847 ◽

2000 ◽

Vol 18 (4) ◽

pp. 847-847 ◽

Cited By ~ 199

Author(s):

Terrence Shaneyfelt ◽

Rozita Husein ◽

Glenn Bubley ◽

Christos S. Mantzoros

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Confidence Interval ◽

Population Distribution ◽

Serum Insulin ◽

Meta Analysis ◽

Prostate Cancer Risk ◽

Sex Hormone Binding Globulin ◽

Total Testosterone

PURPOSE: Although there is strong circumstantial evidence that androgens are implicated in the etiology of prostate cancer, epidemiologic investigations have failed to demonstrate consistently that one or more steroid hormones are implicated. In contrast, recent epidemiologic studies unequivocally link serum insulin-like growth factor 1 (IGF-1) levels with risk for prostate cancer. METHODS: We have performed the first meta-analysis of all previously published studies on hormonal predictors of risk for prostate cancer. RESULTS: A meta-analysis restricted to studies that performed mutual adjustment for all measured serum hormones, age, and body mass index indicated that men whose total testosterone is in the highest quartile are 2.34 times more likely to develop prostate cancer (95% confidence interval, 1.30 to 4.20). In contrast, levels of dihydrotestosterone and estradiol do not seem to play a role of equal importance. The only study that provides multivariably adjusted sex hormone–binding globulin data indicates that this binding protein is inversely related to prostate cancer risk (odds ratio, 0.46; 95% confidence interval, 0.24 to 0.89). Finally, all three studies that examined the role of serum IGF-1 have consistently demonstrated a positive and significant association with prostate cancer risk that is similar in magnitude to that of testosterone. CONCLUSION: Men with either serum testosterone or IGF-1 levels in upper quartile of the population distribution have an approximately two-fold higher risk for developing prostate cancer.

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