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Glutathione S-transferase M1, T1 and P1 gene polymorphisms and the risk of developing type 2 diabetes mellitus in Egyptian diabetic patients with and without diabetic vascular complications. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2014.03.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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Ding F, Li JP, Zhang Y, Qi GH, Song ZC, Yu YH. Comprehensive Analysis of the Association Between the rs1138272 Polymorphism of the GSTP1 Gene and Cancer Susceptibility. Front Physiol 2019; 9:1897. [PMID: 30740061 PMCID: PMC6355699 DOI: 10.3389/fphys.2018.01897] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 12/18/2018] [Indexed: 12/26/2022] Open
Abstract
Background: We obtained conflicting results regarding the relationship between the genetic role of the rs1138272 C/T polymorphism of the GSTP1 (Glutathione S-Transferase pi) gene and the risk of various cancers. Methods: Using the presently available data, a meta-analysis was conducted to comprehensively evaluate the genetic relationship between the GSTP1 rs1138272 polymorphism and cancer susceptibility. Results: A total of 43 studies including 15,688 cases and 17,143 controls were recruited into our quantitative synthesis. In the overall population, we observed an increased risk of overall cancer cases, compared with unrelated controls, in the genetic models of allele T vs. allele C (P-association = 0.007, OR = 1.17), carrier T vs. carrier C (P-association = 0.035, OR = 1.11), TT vs. CC (P-association = 0.002, OR = 1.45), TT vs. CC+CT (P-association = 0.009, OR = 1.42), and CT+TT vs. CC (P-association = 0.027, OR = 1.13). We detected similar positive results within the Asian population. Additionally, there was a significant increase in the incidence of cancer for Africans under all genetic models (all P-association < 0.05, OR > 1). When targeting the Caucasian population, we detected a positive association with the TT vs. CC and TT vs. CC+CT models in the “Colorectal cancer” (P-association < 0.05, OR < 1) and “Head and neck cancer” (P-association < 0.05, OR > 1) subgroups. For the “Lung cancer” subgroup, we observed a slightly increased risk in Caucasians under the models of allele T vs. allele C, carrier T vs. carrier C, CT vs. CC, and CT+TT vs. CC (P-association < 0.05, OR > 1). Conclusion: The TT genotype of the GSTP1 rs1138272 polymorphism is likely related to the susceptibility to overall cancer in the Asian and African populations and, specifically, “Colorectal” and “Head and neck” cancers in the Caucasian population. In addition, the CT genotype of the GSTP1 rs1138272 polymorphism may be linked to the risk of lung cancer in Caucasians. Additional evidence is required to confirm this conclusion.
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Affiliation(s)
- Fei Ding
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong University, Jinan, China.,Second Department of Oncology, The First Hospital of Zibo, Zibo, China
| | - Jin-Ping Li
- Department of Public Health, The First Hospital of Zibo, Zibo, China
| | - Yong Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
| | - Guang-Hui Qi
- Department of Urology Surgery, The First Hospital of Zibo, Zibo, China
| | - Zhi-Chao Song
- Department of Anorectal Surgery, The First Hospital of Zibo, Zibo, China
| | - Yong-Hua Yu
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong University, Jinan, China.,Shandong Academy of Medical Sciences, Jinan, China
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Du L, Lei L, Zhao X, He H, Chen E, Dong J, Zeng Y, Yang J. The Interaction of Smoking with Gene Polymorphisms on Four Digestive Cancers: A Systematic Review and Meta-Analysis. J Cancer 2018; 9:1506-1517. [PMID: 29721061 PMCID: PMC5929096 DOI: 10.7150/jca.22797] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 01/22/2018] [Indexed: 12/15/2022] Open
Abstract
The main purpose of this study was to perform a meta-analysis to assess the interaction between smoking and nine genes (GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, SULT1A1, hOGG1, XRCC1 and p53) on colorectal cancer, gastric cancer, liver cancer and oesophageal cancer. Published articles from the PubMed, ISI and EMBASE databases were retrieved. A total of 67 case-control studies or nested case-control studies were identified for the analysis. The pooled jodds ratio (OR) with 95% confidence interval (CI) was calculated using the random effect model. The overall study showed that the GSTM1 polymorphism was associated with the risk of the four digestive cancers among Asian population (OR 1.284, 95% CI: 1.122-1.470, p: 0). Subgroup analyses by cancer site showed that GSTM1 null genotype increased the gastric cancer risk in total population (OR 1.335, 95% CI: 1.145-1.556, p: 0). However, the association of GSTM1 null genotype with the oesophageal cancer risk was found in smokers (OR 1.382, 95% CI: 1.009-1.894, p:0.044), but not in non-smokers (OR 1.250, 95% CI: 0.826-1.891, p:0.290). Moreover, smokers with the CYP1A1 IIe462Val polymorphism were at an increased cancer risk in Asian population (OR=1.585, 95% CI 1.029-2.442, p: 0.037). None of the other gene-smoking interactions was observed in the above cancers. This meta-analysis reveals two potential gene-smoking interactions, one is between smoking and GSTM1 on oesophageal cancer, and the other is between smoking and CYP1A1 IIe462Val on the four cancers in Asian population. Future studies need to be conducted to verify the conclusions.
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Affiliation(s)
- Le Du
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Lei Lei
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Xiaojuan Zhao
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Hongjuan He
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Erfei Chen
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Jing Dong
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Yuan Zeng
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Jin Yang
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
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Abstract
In first part of this study, a systematic review was designed to explore the involvement of CYP1A1 and GSTP1 genes in breast cancerogenesis. Based on systematic review, we designed a study to screen CYP1A1 and GSTP1 genes for mutation and their possible association with breast carcinogenesis. A total of 400 individuals were collected and analyzed by PCR-SSCP. After sequence analysis of coding region of CYP1A1 we identified eleven mutations in different exons of respective gene. Among these eleven mutations, ~3 folds increased breast cancer risk was found associated with Asp82Glu mutation (OR 2.99; 95% CI 1.26-7.09), with Ser83Thr mutation (OR 2.99; 95% CI 1.26-7.09) and with Glu86Ala mutation (OR 3.18; 95% CI 1.27-7.93) in cancer patients compared to controls. Furthermore, ~4 folds increase in breast cancer risk was found associated with Asp347Glu, Phe398Tyr and 5178delT mutations (OR 3.92; 95% CI 1.35-11.3) in patients compared to controls. The sequence analysis of GSTP1 resulted in identification of total five mutations. Among these five mutations, ~3 folds increase in breast cancer risk was observed associated with 1860G>A mutation, with 1861-1876delCAGCCCTCTGGAGTGG mutation (OR 2.70; 95% CI 1.10-6.62) and with 1861C>A mutation (OR 2.97; 95% CI 1.01-8.45) in cancer patients compared to controls. Furthermore, ~5 folds increase in breast cancer risk was associated with 1883G>T mutation (OR 4.75; 95% CI 1.46-15.3) and ~6 folds increase in breast cancer risk was found associated with Iso105Val mutation (OR 6.43; 95% CI 1.41-29.3) in cancer patients compared to controls. Our finding, based on systematic review and experimental data suggest that the polymorphic CYP1A1 and GSTP1 genes may contribute to risk of developing breast cancer.
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Carrick DM, Black A, Gohagan JK, Khan A, Pettit K, Williams C, Yu K, Yurgalevitch S, Huang WY, Zhu C. The PLCO Biorepository: Creating, Maintaining, and Administering a Unique Biospecimen Resource. Rev Recent Clin Trials 2016; 10:212-22. [PMID: 26238117 DOI: 10.2174/1574887110666150730121429] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 07/14/2015] [Accepted: 07/16/2015] [Indexed: 12/12/2022]
Abstract
Inclusion of biospecimens in population-based studies is an integral part of understanding disease etiology, identifying biomarkers and developing prevention and treatment strategies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial collected, processed and stored biospecimens from participants to create a biorepository of specimens which serves as a useful resource for a broad research community. PLCO collected blood samples from consented screening arm participants at six screening rounds and a buccal sample from consented control arm participants. In addition, formalin-fixed paraffin embedded tumor tissue specimens were collected for participants in both arms for selected cancer sites. Collection of biospecimens at multiple timepoints (i.e. serial samples) and prior to cancer diagnosis, paired with rich epidemiologic and screening data, makes the PLCO collection of biospecimens a uniquely valuable resource. As such, access to the PLCO biorepository is granted to investigators by a rigorous scientific review process and guided by a steering committee which is responsible for developing and implementing the biospecimen use policies. Here, we describe the procedures for biospecimen collection, processing, storage, requisition, and distribution, as well as data management employed in PLCO. We also provide examples of how the biospecimens have been used to advance cancer research and describe relevant lessons learned to help inform cohorts wishing to add or modify biospecimen collection.
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Affiliation(s)
- Danielle M Carrick
- Epidemiology and Genomics Research Program DCCPS, NCI, NIH, 9609 Medical Center Drive 4E224 Rockville, MD 20850, USA.
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Single-Nucleotide Polymorphisms and Markers of Oxidative Stress in Healthy Women. PLoS One 2016; 11:e0156450. [PMID: 27271305 PMCID: PMC4896456 DOI: 10.1371/journal.pone.0156450] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 05/13/2016] [Indexed: 12/22/2022] Open
Abstract
Purpose There is accumulating evidence that oxidative stress is an important contributor to carcinogenesis. We hypothesized that genetic variation in genes involved in maintaining antioxidant/oxidant balance would be associated with overall oxidative stress. Methods We examined associations between single nucleotide polymorphisms (SNPs) in MnSOD, GSTP1, GSTM1, GPX1, GPX3, and CAT genes and thiobarbituric acid-reactive substances (TBARS), a blood biomarker of oxidative damage, in healthy white women randomly selected from Western New York (n = 1402). We used general linear models to calculate age-adjusted geometric means of TBARS across the variants. We also examined the associations within strata of menopausal status. Results For MnSOD, being heterozygous was associated with lower geometric means of TBARS (less oxidative stress), 1.28 mg/dL, compared to homozygous T-allele or homozygous C-allele,1.35 mg/dL, and 1.31 mg/dL correspondingly (p for trend = 0.01). This difference remained among postmenopausal women, 1.40 mg/dL for TT, 1.32 mg/dL for TC, and 1.34mg/dL for CC (p for trend 0.015); it was attenuated among premenopausal women. SNPs in the other genes examined (GSTP1, GSTM1, GPX1, GPX3, and CAT) were not associated with TBARS. Conclusions Our findings suggest that genetic variation in MnSOD gene may be associated with oxidative status, particularly among postmenopausal women.
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Karagulle S, Kalaylioglu Z. A test for detecting etiologic heterogeneity in epidemiological studies. J Appl Stat 2015. [DOI: 10.1080/02664763.2015.1070808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Association of DCC, MLH1, GSTT1, GSTM1, and TP53 gene polymorphisms with colorectal cancer in Kazakhstan. Tumour Biol 2014; 36:279-89. [PMID: 25249451 DOI: 10.1007/s13277-014-2641-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 09/15/2014] [Indexed: 12/16/2022] Open
Abstract
This study presents the first results of a molecular-genetic study of colorectal cancer (CRC) in Kazakhstan. Blood samples were collected from patients diagnosed with rectal or colon cancer (249 individuals) as well as a control cohort of healthy volunteers (245 individuals), taking into account the age, gender, ethnicity, and smoking habits of the CRC patients. Combined analysis of data obtained from individuals of either Kazakh or Russian decent showed a significant association with increased CRC risk in the following genotypes: DCC (32008376G/G and G/A versus A/A; OR = 3.45, 95 % confidence interval (95 %CI) = 1.75-6.81, χ (2) = 14.07, p < 0.0002), MLH1 (-93G/G versus G/A and A/A; OR = 1.45, 95 %CI = 1.02-2.07, χ (2) = 4.21, p < 0.04), TP53 (Pro72Pro; OR = 3.80, 95 %CI = 2.46-5.88, χ (2) = 61.27, p < 0.0001), combination GSTT1 deletions with heterozygotes versus normal homozygotes (OR = 1.43, 95 %CI = 1.00-2.04, χ (2) = 3.90, p < 0.05), and GSTM1 deletions (OR = 1.83, 95 %CI = 1.28-2.63, χ (2) = 11.04, p < .001). Analysis for ethnicity and smoking for each of the investigated polymorphisms showed that some genotypes can have a predictive value for susceptibility to CRC, at least those that demonstrate statistically significant ORs either for the combined mixed population of Kazakhstan or for both main ethnic groups separately (Kazakhs and Russians): TP53 Pro72Pro homozygous (for Kazakh-OR = 3.40, 95 %CI = 1.63-7.06, χ (2) = 11.35, p < 0.003; for Russian-OR = 4.69, 95 %CI = 2.53-8.66, χ (2) = 53.19, p < 0.0001) and GSTM1 deletions (for Kazakh-OR = 2.30, 95 %CI = 1.21-4.40, χ (2) = 8.42, p < 0.01; for Russian-OR = 1.64, 95 %CI = 1.01-2.66, χ (2) = 7.82, p < 0.02).
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Senthilkumar KP, Thirumurugan R. Risk modulation of GSTM1–GSTT1 interactions to head and neck cancer in tobacco users. Mol Biol Rep 2014; 41:5635-44. [PMID: 25015263 DOI: 10.1007/s11033-014-3433-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 05/24/2014] [Indexed: 12/15/2022]
Abstract
Tobacco use and environmental air pollution are the established etiological factors in head and neck cancer (HNC) progression. Nevertheless, not all the inhabitants with high usage of tobacco from the same polluted locality are suffering with HNC and this is due to the existence of factors like inter-individual genetic polymorphisms, life time exposure to tobacco and the rate of xenobiotic metabolism enzyme (XME) activity. The present study investigates the polymorphic genotypes of the most important XME, glutathione-S-transferase Mu 1 (GST M1) and Theta 1 (GST T1) as the risk modulator to HNC among tobacco-habituated inhabitants of Saurashtra in Gujarat, a region in western India. A population based case–control study was done in 252 HNC patients and 504 healthy controls. Blood samples were collected from the subjects and investigated for polymorphic genotypes of GST M1 and GST T1. Estimation of the odds of risks was done by logistic regressions. Among the subjects with high usage of tobacco, M1 not null-T1 null genotypes presence was found as risk reducing factor to HNC with 0.334 folds (95 % CI; 0.170-0.659). The presence of M1 null-T1 not null genotypes was found with susceptibility to HNC among the subjects with no habit of tobacco chewing, adjusted odds ratio (AOR) 3.170 (1.128-8.913) and no habit of smoking, AOR of 2.544 (1.094-5.963). The present study reveals the finding of significantly increased risk to HNC by interactions of GST M1 null-GST T1 not null polymorphic genotypes among the subjects with nil or less tobacco usage shed some light for the insights of biomarker application in early detection of HNC.
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Correlates of self-reported dietary cruciferous vegetable intake and urinary isothiocyanate from two cohorts in China. Public Health Nutr 2014; 18:1237-44. [PMID: 25098275 DOI: 10.1017/s1368980014001505] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE To assess correlations between cruciferous vegetable intake and urinary isothiocyanate (ITC) level, in addition to glutathione S-transferase (GST) genotypes and other individual factors. DESIGN The study included cohort participants whose urinary ITC levels had been previously ascertained. Urinary ITC was assessed using HPLC. Usual dietary intake of cruciferous vegetables was assessed using a validated FFQ and total dietary ITC intake was calculated. Recent cruciferous vegetable intake was determined. GST genotypes were assessed using duplex real-time quantitative PCR assays. Spearman correlations were calculated between the covariates and urinary ITC levels and linear regression analyses were used to calculate the mean urinary ITC excretion according to GST genotype. SETTING Urban city in China. SUBJECTS The study included 3589 women and 1015 men from the Shanghai Women's and Men's Health Studies. RESULTS Median urinary ITC level was 1.61 nmol/mg creatinine. Self-reported usual cruciferous vegetable intake was weakly correlated with urinary ITC level (r s=0.1149; P<0.0001), while self-reported recent intake was more strongly correlated with urinary ITC (r s=0.2591; P<0.0001). Overall, the GST genotypes were not associated with urinary ITC level, but significant differences according to genotype were observed among current smokers and participants who provided an afternoon urine sample. Other factors, including previous gastrectomy or gastritis, were also related to urinary ITC level. CONCLUSIONS The study suggests that urinary secretion of ITC may provide additional information on cruciferous vegetable intake and that GST genotypes are related to urinary ITC level only in some subgroups.
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Jiang Y, Wu SH, Shu XO, Xiang YB, Ji BT, Milne GL, Cai Q, Zhang X, Gao YT, Zheng W, Yang G. Cruciferous vegetable intake is inversely correlated with circulating levels of proinflammatory markers in women. J Acad Nutr Diet 2014; 114:700-8.e2. [PMID: 24630682 PMCID: PMC4063312 DOI: 10.1016/j.jand.2013.12.019] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 12/10/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND Higher intakes of cruciferous vegetables or their constituents have been shown to lower inflammation in animal studies. However, evidence for this anti-inflammatory effect of cruciferous vegetable consumption in humans is scarce. OBJECTIVE/DESIGN In this cross-sectional analysis, we evaluated associations of vegetable intake with a panel of inflammatory and oxidative stress markers among 1,005 middle-aged Chinese women. Dietary intake of foods was assessed by a food frequency questionnaire. RESULTS Multivariable-adjusted circulating concentrations of tumor necrosis factor-α (TNF-α), interlukin-1β (IL-1β), and IL-6 were lower among women with higher intakes of cruciferous vegetables. The differences in concentrations of inflammatory biomarkers between extreme quintiles of cruciferous vegetable intake were 12.66% for TNF-α (Ptrend=0.01), 18.18% for IL-1β (Ptrend=0.02), and 24.68% for IL-6 (Ptrend=0.02). A similar, but less apparent, inverse association was found for intakes of all vegetables combined but not for noncruciferous vegetables. Levels of the urinary oxidative stress markers F2-isoprostanes and their major metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP, were not associated with intakes of cruciferous vegetables or all vegetables combined. CONCLUSIONS This study suggests that the previously observed health benefits of cruciferous vegetable consumption may be partly associated with the anti-inflammatory effects of these vegetables.
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Yamada I, Matsuyama M, Ozaka M, Inoue D, Muramatsu Y, Ishii H, Junko U, Ueno M, Egawa N, Nakao H, Mori M, Matsuo K, Nishiyama T, Ohkawa S, Hosono S, Wakai K, Nakamura K, Tamakoshi A, Kuruma S, Nojima M, Takahashi M, Shimada K, Yagyu K, Kikuchi S, Lin Y. Lack of Associations between Genetic Polymorphisms in GSTM1, GSTT1 and GSTP1 and Pancreatic Cancer Risk: A Multi-Institutional Case-Control Study in Japan. Asian Pac J Cancer Prev 2014; 15:391-5. [DOI: 10.7314/apjcp.2014.15.1.391] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Bernig T, Chanock SJ. Challenges of SNP genotyping and genetic variation: its future role in diagnosis and treatment of cancer. Expert Rev Mol Diagn 2014; 6:319-31. [PMID: 16706736 DOI: 10.1586/14737159.6.3.319] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Thorough annotation of common germline genetic variation in the human genome has generated a foundation for the investigation of the contribution of genetics to the etiology and pathogenesis of cancer. For many malignancies, it has become increasingly apparent that numerous alleles, with small-to-moderate effects, additively contribute to cancer susceptibility. The most common genetic variant in the genome, the single nucleotide polymorphism, is of special interest for the study of susceptibility to and protection from cancer. Similarly, intense effort has focused on genetic variants that can predict either response or toxicity to therapeutic interventions. This review discusses the challenges and prospects of genetic association studies in cancer research. On the basis of recent changes in genomics and high-throughput genotyping platforms, future genetic findings of association studies could impact clinical care and public health screening.
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Affiliation(s)
- Toralf Bernig
- National Cancer Institute, Section on Genomic Variation, Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD 20892-4605, USA.
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Vogtmann E, Xiang YB, Li HL, Cai Q, Wu QJ, Xie L, Li GL, Yang G, Waterbor JW, Levitan EB, Zhang B, Zheng W, Shu XO. Cruciferous vegetables, glutathione S-transferase polymorphisms, and the risk of colorectal cancer among Chinese men. Ann Epidemiol 2014; 24:44-9. [PMID: 24238877 PMCID: PMC3864981 DOI: 10.1016/j.annepidem.2013.10.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 09/16/2013] [Accepted: 10/08/2013] [Indexed: 02/07/2023]
Abstract
PURPOSE To assess the associations between cruciferous vegetable (CV) intake, GST gene polymorphisms, and colorectal cancer (CRC) in a population of Chinese men. METHODS Using incidence density sampling, CRC cases (N = 340) diagnosed before December 31, 2010 within the Shanghai Men's Health Study were matched to noncases (N = 673). CV intake was assessed from a food frequency questionnaire and by isothiocyanate levels from spot urine samples. GSTM1 and GSTT1 were categorized as null (0 copies) versus non-null (1 or 2 copies). Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association between CV intake and GST gene variants with CRC, and statistical interactions were evaluated. RESULTS CRC risk was not associated with CV intake, whether measured by self-report or by urinary isothiocyanate nor with GST gene variants. No statistical interactions were detected between CV intake and GST gene variants on the odds of CRC. Stratifying by timing of urine sample collection and excluding CRC cases diagnosed in the first 2 years did not materially alter the results. CONCLUSIONS This study provides no evidence supporting the involvement of CV intake in the development of CRC in Chinese men.
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Affiliation(s)
- Emily Vogtmann
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville TN, USA
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham AL, USA
| | - Yong-Bing Xiang
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hong-Lan Li
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Quiyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville TN, USA
| | - Qi-Jun Wu
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Li Xie
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guo-Liang Li
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville TN, USA
| | - Gong Yang
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville TN, USA
| | - John W. Waterbor
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham AL, USA
| | - Emily B. Levitan
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham AL, USA
| | - Bin Zhang
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville TN, USA
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville TN, USA
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Hamachi T, Tajima O, Uezono K, Tabata S, Abe H, Ohnaka K, Kono S. CYP1A1, GSTM1, GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men. World J Gastroenterol 2013; 19:4023-4030. [PMID: 23840148 PMCID: PMC3703190 DOI: 10.3748/wjg.v19.i25.4023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Accepted: 04/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of functional genetic polymorphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas.
METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied were CYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other lifestyle factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test.
RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1. A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There was no measurable effect modification of smoking even regarding the combination of the genetic polymorphisms of the phase I and phase II enzymes.
CONCLUSION: Combination of the CYP1A1*2C and NQO1 609CC genotypes was associated with a decreased risk of colorectal adenomas regardless of smoking status.
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Huang SX, Wu FX, Luo M, Ma L, Gao KF, Li J, Wu WJ, Huang S, Yang Q, Liu K, Zhao YN, Li LQ. The glutathione S-transferase P1 341C>T polymorphism and cancer risk: a meta-analysis of 28 case-control studies. PLoS One 2013; 8:e56722. [PMID: 23437223 PMCID: PMC3578943 DOI: 10.1371/journal.pone.0056722] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2012] [Accepted: 01/14/2013] [Indexed: 01/01/2023] Open
Abstract
Background GSTP1, which is one major group of the glutathione S-transferase family, plays an important role in the metabolism of carcinogens and toxins, reducing damage of DNA as a suppressor of carcinogenesis. The 341C>T polymorphism of the GSTP1 has been implicated in cancer risk through cutting down its metabolic detoxification activities. However, results from previous studies remain conflicting rather than conclusive. To clarify the correlation and provide more statistical evidence for detecting the significance of 341C>T, a meta-analysis was conducted. Methodology/Principal Findings The relevant studies were identified through searching of PubMed, Embase, ISI Web of Knowledge and China National Knowledge Infrastructure in August 2012, and selected based on the established inclusion criteria for publications, then a meta-analysis was performed to quantitatively summarize the association of GSTP1 341C>T polymorphism with cancer susceptibility. Stratified analyses were employed to identify the source of heterogeneity. Publication bias was evaluated as well as sensitivity analysis. Based on 28 case-control studies with 13249 cases and 16798 controls, the pooled results indicated that the variant genotypes significantly increased the risk of cancer in homozygote comparison (TT versus CC: P = 0.012, OR = 1.40, 95% CI: 1.08–1.81, Phet. = 0.575), and recessive model (TT versus CT/CC: P = 0.012, OR = 1.40, 95% CI: 1.08–1.81, Phet. = 0.562). This was confirmed when stratified analyses were conducted according to ethnicity, source of control, matched control, quality score and cancer types. Moreover, significantly increased risk of cancer was also found in lung cancer (heterozygote comparison and dominant model). The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias. Conclusions/Significance This meta-analysis suggests that the GSTP1 341C>T polymorphism may contribute to genetic susceptibility to cancer, especially to lung cancer, and in Asian population. Nevertheless, additional well-designed studies focusing on different ethnicity and cancer types are needed to provide a more exact and comprehensive conclusion.
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Affiliation(s)
- Sheng-xin Huang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Fei-xiang Wu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Min Luo
- Department of Experiment, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Liang Ma
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Ke-feng Gao
- Department of Thoracic Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Jian Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Wen-juan Wu
- Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Shan Huang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Qi Yang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Ke Liu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Yin-nong Zhao
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Le-qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
- * E-mail:
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Theodoratou E, Montazeri Z, Hawken S, Allum GC, Gong J, Tait V, Kirac I, Tazari M, Farrington SM, Demarsh A, Zgaga L, Landry D, Benson HE, Read SH, Rudan I, Tenesa A, Dunlop MG, Campbell H, Little J. Systematic Meta-Analyses and Field Synopsis of Genetic Association Studies in Colorectal Cancer. J Natl Cancer Inst 2012; 104:1433-57. [DOI: 10.1093/jnci/djs369] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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18
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Luo J, Gao YT, Chow WH, Shu XO, Li H, Yang G, Cai Q, Li G, Rothman N, Cai H, Shrubsole MJ, Franke AA, Zheng W, Dai Q. Urinary polyphenols, glutathione S-transferases copy number variation, and breast cancer risk: results from the Shanghai women's health study. Mol Carcinog 2012; 51:379-88. [PMID: 21557334 PMCID: PMC3257420 DOI: 10.1002/mc.20799] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Revised: 04/06/2011] [Accepted: 04/20/2011] [Indexed: 11/11/2022]
Abstract
In vitro studies have found that flavanol epigallocatechin (EGC) and flavonols, but not flavanol epicatechin (EC), activate glutathione S-transferases (GSTs), a family of phase II enzymes that detoxify reactive oxygen species, such as catechol estrogen metabolites. This study was designed to investigate prospectively whether urinary excretion of tea polyphenols interacts with GST polymorphisms to influence breast cancer risk. We conducted a study of 352 incident breast cancer cases and 701 individually matched controls nested within the Shanghai Women's Health Study cohort of women aged 40-70 yr at baseline. Liquid chromatography tandem mass spectrometry was used to measure urinary excretion of flavanols and flavonols. Real-time multiplex PCR was used to quantify the copy number variation in the GSTM1 and GSTT1 genes. Urinary excretion of flavonols and flavanols, particularly EGC (P = 0.02), was significantly higher among women null for GSTM1 than those positive for GSTM1. Flavonols and flavanols (EGC in particular) were associated with a reduced risk of breast cancer among those null for GSTM1 and GSTT1, with a P-value of 0.04 for the interaction between EGC and GSTM1 polymorphism. In contrast, among women possessing both GSTM1 and GSTT1, breast cancer risk increased with levels of flavonols, particularly kaempferol. The differential associations between polyphenols and breast cancer risk by GST polymorphisms, if confirmed, may provide a new avenue for the personalized prevention of breast cancer.
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Affiliation(s)
- Jianfeng Luo
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
- Department of Health Statistics and Social Medicine, School of Public Health, Fudan University, Shanghai 200032, China (Key Laboratory of Public Health Safety, Ministry of Education (Fudan University))
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Wong-Ho Chow
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland
| | - Xiao-ou Shu
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
| | - Honglan Li
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Gong Yang
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
| | - Qiuyin Cai
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
| | - Guoliang Li
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland
| | - Hui Cai
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
| | - Martha J. Shrubsole
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
| | - Adrian A Franke
- Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii 96813
| | - Wei Zheng
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
| | - Qi Dai
- Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
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19
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Buchard A, Eefsen M, Semb S, Andersen SE, Morling N, Bendtsen F, Larsen FS, Dalhoff K. The role of the glutathione S-transferase genes GSTT1, GSTM1, and GSTP1 in acetaminophen-poisoned patients. Clin Toxicol (Phila) 2011; 50:27-33. [DOI: 10.3109/15563650.2011.639713] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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20
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Zhao ZQ, Guan QK, Yang FY, Zhao P, Zhou B, Chen ZJ. System review and metaanalysis of the relationships between five metabolic gene polymorphisms and colorectal adenoma risk. Tumour Biol 2011; 33:523-35. [PMID: 22161138 DOI: 10.1007/s13277-011-0287-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2011] [Accepted: 11/23/2011] [Indexed: 01/30/2023] Open
Abstract
The relationships between some metabolic (including EPHX1, GSTs and NQO1) gene polymorphisms and colorectal adenoma (CRA) risk have been commonly studied, and no conclusions are available up to now. Therefore, we quantitatively studied the relationships by a metaanalysis. The databases of Medline and Embase were retrieved updated to June 15th, 2011. Crude or adjusted odds ratio (crude OR or adjusted OR) and 95% confidence interval (95%CI) were calculated to present the strength of the associations. Overall, nine case-control studies for EPHX1 Tyr113His and His139Arg, five case-control studies for GSTM1, four studies for GSTP1 Ile105Val, two studies for GSTP1 Ala114Val, six studies for GSTT1 and four studies for NQO1 Pro187Ser were included in this metaanalysis. The results of combined analyses indicated that EPHX1 Tyr113His and His139Arg, GSTT1, GSTM1, GSTP1 Ile105Val and Ala114Val were not associated with CRA risk [crude OR (95%CI): 0.98 (0.90-1.07) and P ( z-test) = 0.65 for EPHX1 His carriers vs. Tyr/Tyr; 1.05 (0.97-1.15) and P ( z-test) = 0.21 for EPHX1 Arg carriers vs. His/His; 1.05 (0.92-1.20) and P ( z-test) = 0.47 for GSTT1 Null vs. Present; 1.01 (0.90-1.13) and P ( z-test) = 0.90 for GSTM1 Null vs. Present; 1.04 (0.92-1.17) and P ( z-test) = 0.56 for G carriers vs. AA for GSTP1 Ile105Val; 0.88 (0.70-1.11) and P ( z-test) = 0.28 for T carriers vs. CC for GSTP1 Ala114Val]. In contrast, Ser allele of NQO1 Ser187Pro might be a modest risk factor for CRA development [1.19 (1.06-1.33) and P ( z-test) = 0.003 for Ser carriers vs. Pro/Pro]. To get more precise evidences, adjusted ORs (95%CI) for EPHX1 Tyr113His, His139Arg, GSTP1 Ile105Val and NQO1 Ser187Pro were also calculated based on adjusted ORs (95%CIs) reported in primary studies. The results still indicated that EPHX1 Tyr113His, His139Arg and GSTP1 Ile105Val were not associated with CRA risk except for NQO1 Ser187Pro. When subgroup analyses were performed for population-based case-control studies or studies in HWE for EPHX1 Tyr113His and His139Arg, and NQO1 Ser187Pro polymorphisms, the results were persistent. Although with modest limitations and biases, this metaanalysis suggests that EPHX1 Tyr113His and His139Arg, GSTT1, GSTM1, GSTP1 Ile105Val and Ala114Val polymorphisms may be not risk factors for CRA development, while Ser allele of NQO1 Ser187 Pro may be a modest risk factor for CRA development, and may be used with other genetic markers for screening CRA in the future.
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Affiliation(s)
- Zhi-Qiang Zhao
- Department of Pediatric Surgery, First Affiliated Hospital of Xinxiang Medical University, Health Road No. 88, Weihui City, Henan Province, People's Republic of China
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Koh WP, Nelson HH, Yuan JM, Van den Berg D, Jin A, Wang R, Yu MC. Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore. Carcinogenesis 2011; 32:1507-11. [PMID: 21803734 PMCID: PMC3179426 DOI: 10.1093/carcin/bgr175] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 07/08/2011] [Accepted: 07/23/2011] [Indexed: 12/13/2022] Open
Abstract
Cigarette smoking is a risk factor for colorectal cancer. Putative colorectal procarcinogens in tobacco smoke include polycyclic aromatic hydrocarbons and heterocyclic aromatic amines that are known substrates of glutathione S-transferases (GSTs). This study examined the influence of functional GST gene polymorphisms on the smoking-colorectal cancer association in a population known to be minimally exposed to dietary sources of these procarcinogens. Incident cases of colorectal cancer (n = 480) and matched controls (n = 1167) were selected from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 men and women who have been followed since 1993. We determined the deletion polymorphisms of GSTM1 and GSTT1 and the functional polymorphism at codon 105 of GSTP1 for each subject. A three level composite GST index was used to examine if GST profile affected a smoker's risk of developing colorectal cancer. While there was no statistically significant association between cigarette smoking and colorectal cancer risk among subjects absent of any at-risk GST genotypes, smokers possessing two to three at-risk GST genotypes exhibited a statistically significant increased risk of colorectal cancer compared with non-smokers (P = 0.0002). In this latter stratum, heavy smokers exhibited a >5-fold increased risk relative to never-smokers (odds ratio, 5.43; 95% confidence interval, 2.22-13.23). Subjects with one at-risk GST genotype displayed a statistically significant but weaker association with smoking. These findings suggest that GST gene polymorphisms influence interindividual susceptibility to smoking-associated colorectal cancer. Our data indicate an important role for GST enzymes in the detoxification of colorectal carcinogens in tobacco smoke.
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Affiliation(s)
- Woon-Puay Koh
- Department of Epidemiology and Public Health, National University of Singapore, Singapore.
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22
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Fowke JH, Gao YT, Chow WH, Cai Q, Shu XO, Li HL, Ji BT, Rothman N, Yang G, Chung FL, Zheng W. Urinary isothiocyanate levels and lung cancer risk among non-smoking women: a prospective investigation. Lung Cancer 2011; 73:18-24. [PMID: 21122939 PMCID: PMC3072449 DOI: 10.1016/j.lungcan.2010.10.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 10/26/2010] [Accepted: 10/29/2010] [Indexed: 01/11/2023]
Abstract
BACKGROUND Aside from tobacco carcinogen metabolism, isothiocyanates (ITC) from cruciferous vegetables may induce apoptosis or steroid metabolism to reduce lung cancer risk. To separate the effect of these divergent mechanisms of action, we investigated the association between urinary ITC levels and lung cancer risk among non-smoking women. METHODS We conducted a nested case-control within the Shanghai Women's Health Study. Subjects included 209 incident lung cancer cases who never used tobacco, and 787 individually matched non-smoking controls. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) summarizing the association between urinary ITC levels and lung cancer. Secondary analyses stratified the ITC-lung cancer analyses by menopausal status, exposure to environmental tobacco smoke, and GSTM1 and GSTT1 genotypes. RESULTS Urinary ITC levels were not significantly associated with lower lung cancer risk among non-smoking women, regardless of exposure to environmental tobacco smoke or menopausal status. Furthermore, this association was not modified by GSTT1 genotype. However, an inverse association was suggested among women with a GSTM1-positive genotype (Q1: OR=1.0 (reference); Q2: OR=0.35 (0.14, 0.89); Q3: OR=0.47 (0.20, 1.10); Q4: OR=0.63 (0.35, 1.54), p-trend=0.38). In contrast, lung cancer risk was positively associated with urinary ITC levels among women with the GSTM1-null genotype (Q1: OR=1.0 (reference); Q2: OR=1.67 (0.80, 3.50); Q3: OR=1.54 (0.71, 3.33); Q4: OR=2.22 (1.05, 4.67), p-trend=0.06). CONCLUSION Urinary ITC levels were not associated overall with lower lung cancer risk among non-smoking women, but secondary analyses suggested an interaction between urinary ITC levels, GSTM1 genotype, and lung cancer risk.
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Affiliation(s)
- Jay H Fowke
- Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN 37203-1738, United States.
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Ferrucci LM, Cross AJ, Gunter MJ, Ahn J, Mayne ST, Ma X, Chanock SJ, Yeager M, Graubard BI, Berndt SI, Huang WY, Hayes RB, Sinha R. Xenobiotic metabolizing genes, meat-related exposures, and risk of advanced colorectal adenoma. JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS 2011; 3:170-81. [PMID: 21474949 DOI: 10.1159/000324351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Lea M Ferrucci
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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24
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Dourado DFAR, Fernandes PA, Ramos MJ. Glutathione Transferase Classes Alpha, Pi, and Mu: GSH Activation Mechanism. J Phys Chem B 2010; 114:12972-80. [DOI: 10.1021/jp1053875] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Daniel F. A. R. Dourado
- REQUIMTE/Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
| | - Pedro Alexandrino Fernandes
- REQUIMTE/Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
| | - Maria João Ramos
- REQUIMTE/Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
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Palma S, Novelli F, Padua L, Venuti A, Prignano G, Mariani L, Cozzi R, Tirindelli D, Testa A. Interaction between glutathione-S-transferase polymorphisms, smoking habit, and HPV infection in cervical cancer risk. J Cancer Res Clin Oncol 2010; 136:1101-9. [PMID: 20069434 DOI: 10.1007/s00432-009-0757-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2009] [Accepted: 12/21/2009] [Indexed: 10/20/2022]
Abstract
PURPOSE Human papillomavirus (HPV) infection is considered the major cause of cervical cancer (CC), but a number of infected women do not develop invasive lesions, suggesting the role of genetic susceptibility and environmental co-factors for cancer outbreak. The aim of this study was to investigate whether some GST polymorphisms could influence the risk to develop CC, either by themselves or in combination with smoking habit, in a cohort of high-risk HPV (HR-HPV) infected Italian women. METHODS The study population comprises 192 Italian women including 81 HR-HPV infected women bearing cervical lesions and 111 healthy controls. The cases include: 26 low-grade squamous intraepithelial lesions (LSILs), 30 high-grade-SIL, and 25 CCs, while controls were all negative for HPV. DNA was extracted from peripheral blood samples or cytobrush and individuals were genotyped for GSTM1, GSTT1, and GSTP1 polymorphisms using PCR and PCR/RFLP techniques. RESULTS On studying the association of GSTs gene polymorphisms with cervical cancer lesions, the combination of GSTM1 null, GSTT1 null and GSTP1 AA genotypes, independently on smoking habit, seems to be related to a 5.7-fold increased risk of developing CLs with a considerable statistical significance (P = 0.0091). CONCLUSIONS We suggest that the investigation of multiple gene polymorphisms, versus single genes, could contribute to a better understanding of the effect of susceptibility genes on cancer risk.
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Affiliation(s)
- Selena Palma
- Section Toxicology and Biomedical Sciences, C.R. ENEA Casaccia, Via Anguillarese 301, 00123 Rome, Italy
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McGrath DR, Frydoonfar H, Hunt JJ, Dunkley CJ, Spigelman AD. Serum glutathione transferase does not respond to indole-3-carbinol: A pilot study. Ther Clin Risk Manag 2010; 6:225-31. [PMID: 20526440 PMCID: PMC2878956 DOI: 10.2147/tcrm.s9568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Indexed: 12/02/2022] Open
Abstract
Background: Despite the well recognized protective effect of cruciferous vegetables against various cancers, including human colorectal cancers, little is known about how this effect is conferred. It is thought that some phytochemicals found only in these vegetables confer the protection. These compounds include the glucosinolates, of which indole-3-carbinol is one. They are known to induce carcinogen-metabolizing (phase II) enzymes, including the glutathione S-transferase (GST) family. Other effects in humans are not well documented. We wished to assess the effect of indole-3-carbinol on GST enzymes. Methods: We carried out a placebo-controlled human volunteer study. All patients were given 400 mg daily of indole-3-carbinol for three months, followed by placebo. Serum samples were tested for the GSTM1 genotype by polymerase chain reaction. Serum GST levels were assessed using enzyme-linked immunosorbent assay and Western Blot methodologies. Results: Forty-nine volunteers completed the study. GSTM1 genotypes were obtained for all but two volunteers. A slightly greater proportion of volunteers were GSTM1-positive, in keeping with the general population. GST was detected in all patients. Total GST level was not affected by indole-3-carbinol dosing compared with placebo. Although not statistically significant, the GSTM1 genotype affected the serum GST level response to indole-3-carbinol. Conclusion: Indole-3-carbinol does not alter total serum GST levels during prolonged dosing.
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Northwood EL, Elliott F, Forman D, Barrett JH, Wilkie MJV, Carey FA, Steele RJC, Wolf R, Bishop T, Smith G. Polymorphisms in xenobiotic metabolizing enzymes and diet influence colorectal adenoma risk. Pharmacogenet Genomics 2010; 20:315-26. [PMID: 20375710 DOI: 10.1097/fpc.0b013e3283395c6a] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES We have earlier shown that diet and xenobiotic metabolizing enzyme genotypes influence colorectal cancer risk, and now investigate whether similar associations are seen in patients with premalignant colorectal adenomas (CRA), recruited during the pilot phase of the Scottish Bowel Screening Programme. METHODS Nineteen polymorphisms in 13 genes [cytochrome P450 (P450), glutathione S-transferase (GST), N-acetyl transferase, quinone reductase (NQ01) and microsomal epoxide hydrolase (EPHX1) genes] were genotyped using multiplex PCR or Taqman-based allelic discrimination assays and analyzed in conjunction with diet, assessed by food frequency questionnaire, in a case-control study [317 CRA cases (308 cases genotyped), 296 controls]. Findings significant at a nominal 5% level are reported. RESULTS CRA risk was inversely associated with fruit (P=0.02, test for trend) and vegetable (P=0.001, test for trend) consumption. P450 CYP2C9*3 heterozygotes had reduced CRA risk compared with homozygotes for the reference allele [odds ratio (OR): 0.60; 95% confidence interval (CI): 0.36-0.99], whereas CYP2D6*4 homozygotes (OR: 2.72; 95% CI: 1.18-6.27) and GSTM1 'null' individuals (OR: 1.43; 95% CI: 1.04-1.98) were at increased risk. The protective effect of fruit consumption was confined to GSTP1 (Ala114Val) reference allele homozygotes (OR: 0.49; 95% CI: 0.34-0.71, P=0.03 for interaction). CRA risk was not associated with meat consumption, although a significant interaction between red meat consumption and EPHX1 (His139Arg) genotype was noted (P=0.02 for interaction). CONCLUSION We report the novel associations between P450 genotype and CRA risk, and highlight the risk association with GSTM1 genotype, common to our CRA and cancer case-control series. In addition, we report a novel modifying influence of GSTP1 genotype on dietary chemoprevention. These novel findings require independent confirmation.
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Affiliation(s)
- Emma L Northwood
- Leeds Institute of Molecular Medicine, University of Leeds, St James's University Hospital
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Yang G, Gao YT, Shu XO, Cai Q, Li GL, Li HL, Ji BT, Rothman N, Dyba M, Xiang YB, Chung FL, Chow WH, Zheng W. Isothiocyanate exposure, glutathione S-transferase polymorphisms, and colorectal cancer risk. Am J Clin Nutr 2010; 91:704-11. [PMID: 20042523 PMCID: PMC2824157 DOI: 10.3945/ajcn.2009.28683] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Isothiocyanates, compounds found primarily in cruciferous vegetables, have been shown in laboratory studies to possess anticarcinogenic activity. Glutathione S-transferases (GSTs) are involved in the metabolism and elimination of isothiocyanates; thus, genetic variations in these enzymes may affect in vivo bioavailability and the activity of isothiocyanates. OBJECTIVE The objective was to prospectively evaluate the association between urinary isothiocyanate concentrations and colorectal cancer risk as well as the potential modifying effect of GST genotypes on the association. DESIGN A nested case-control study of 322 cases and 1251 controls identified from the Shanghai Women's Health Study was conducted. RESULTS Urinary isothiocyanate concentrations were inversely associated with colorectal cancer risk; the inverse association was statistically significant or nearly significant in the GSTM1-null (P for trend = 0.04) and the GSTT1-null (P for trend = 0.07) genotype groups. The strongest inverse association was found among individuals with both the GSTM1-null and the GSTT1-null genotypes, with an adjusted odds ratio of 0.51 (95% CI: 0.27, 0.95), in a comparison of the highest with the lowest tertile of urinary isothiocyanates. No apparent associations between isothiocyanate concentration and colorectal cancer risk were found among individuals who carried either the GSTM1 or GSTT1 gene (P for interaction < 0.05). CONCLUSION This study suggests that isothiocyanate exposure may reduce the risk of colorectal cancer, and this protective effect may be modified by the GSTM1 and GSTT1 genes.
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Affiliation(s)
- Gong Yang
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
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Wang S, Chanock S, Tang D, Li Z, Edwards S, Jedrychowski W, Perera FP. Effect of gene-environment Interactions on mental development in African American, Dominican, and Caucasian mothers and newborns. Ann Hum Genet 2010; 74:46-56. [PMID: 19860743 PMCID: PMC2804781 DOI: 10.1111/j.1469-1809.2009.00550.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The health impact of environmental toxins has gained increasing recognition over the years. Polycyclic aromatic hydrocarbons (PAHs) and environmental tobacco smoke (ETS) are known to affect nervous system development in children, but no studies have investigated how polymorphisms in PAH metabolic genes affect child cognitive development following PAH exposure during pregnancy. In two parallel prospective cohort studies of non-smoking African American and Dominican mothers and children in New York City and of Caucasian mothers and children in Krakow, Poland, we explored the effect of gene-PAH interaction on child mental development index (MDI). Genes known to play important roles in the metabolic activation or detoxification of PAHs were selected. Genetic variations in these genes could influence susceptibility to adverse effects of PAHs in polluted air. We explored the effects of interactions between prenatal PAH exposure and 21 polymorphisms or haplotypes in these genes on MDI at 12, 24, and 36 months among 547 newborns and 806 mothers from three different ethnic groups. Significant interaction effects between haplotypes and PAHs were observed in mothers and their newborns in all three ethnic groups after Bonferroni correction. The strongest and most consistent effect observed was between PAH and haplotype ACCGGC of the CYP1B1 gene.
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Affiliation(s)
- Shuang Wang
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY
| | | | - Deliang Tang
- Columbia Center for Children’s Environmental Health, Columbia University, New York, NY
| | - Zhigang Li
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY
| | - Susan Edwards
- Columbia Center for Children’s Environmental Health, Columbia University, New York, NY
| | - Wieslaw Jedrychowski
- Columbia Center for Children’s Environmental Health, Columbia University, New York, NY
- Department of Epidemiology and Preventive Medicine, Collage of Medicine, Jagiellonian University, Krakow, Poland
| | - Frederica P. Perera
- Columbia Center for Children’s Environmental Health, Columbia University, New York, NY
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Piao JM, Shin MH, Kweon SS, Kim HN, Choi JS, Bae WK, Shim HJ, Kim HR, Park YK, Choi YD, Kim SH. Glutathione-S-transferase (GSTM1, GSTT1) and the risk of gastrointestinal cancer in a Korean population. World J Gastroenterol 2009; 15:5716-21. [PMID: 19960570 PMCID: PMC2789226 DOI: 10.3748/wjg.15.5716] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the association of glutathione S-transferase mu (GSTM1) and glutathione S-transferase theta (GSTT1) null genotypes with the risk of gastric cancer (GC) and colorectal cancer (CRC) in a South Korean population.
METHODS: We conducted a population-based, large-scale case-control study including 2213 GCs, 1829 CRCs, and 1699 controls. Null and non-null genotypes of GSTM1 and GSTT1 were determined using real-time PCR.
RESULTS: The null genotypes of GSTM1 and GSTT1 were not significantly associated with elevated risk of gastric (OR = 1.070, 95% CI = 0.935-1.224; OR = 1.101, 95% CI = 0.963-1.259, respectively) or colorectal cancer (OR = 1.065, 95% CI = 0.923-1.228; OR = 1.041, 95% CI = 0.903-1.200, respectively). The frequency of the combined null GST genotype was not different between the two cancer groups and controls. Moreover, smoking, drinking, and age did not modify the association between these genotypes and the risk of gastric or colorectal cancer.
CONCLUSION: GSTM1 and GSTT1 null genotypes were not associated with increased risk of GC or CRC in Koreans.
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Reply. Cancer Epidemiol Biomarkers Prev 2009. [DOI: 10.1158/1055-9965.epi-09-0794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Lam TK, Ruczinski I, Helzlsouer K, Shugart YY, Li KE, Clipp S, Strickland PT, Alberg AJ. Copy number variants of GSTM1 and GSTT1 in relation to lung cancer risk in a prospective cohort study. Ann Epidemiol 2009; 19:546-52. [PMID: 19394866 PMCID: PMC2720160 DOI: 10.1016/j.annepidem.2009.03.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2008] [Revised: 02/26/2009] [Accepted: 03/01/2009] [Indexed: 01/10/2023]
Abstract
PURPOSE Previous studies did not discriminate wild-type from hemizygous genotypes of GSTM1 and GSTT1. In this study, we investigated wild-type, hemizygous deletion, and homozygous deletion genotypes of GSTM1 and GSTT1 and lung cancer risk. METHODS We conducted a nested case-control study of 143 primary incident lung cancer cases matched to 447 cancer-free controls. Genotyping was carried out using a real-time polymerase chain reaction (PCR)-based assay. Conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS Compared to GSTM1 wild-type carriers, the relative odds of lung cancer increased from 1.49 (95% CI=0.66-3.40) to 1.80 (95% CI=0.81-4.02) for the hemizygous and homozygous deletion genotypes, respectively (p-trend=0.13). The strongest associations were seen among those who smoked less than one pack per day and had greater than or equal to one deletion variant of GSTM1 (OR=3.25; 95% CI=0.93-11.34; p-trend=0.07) whereas the reverse was observed for smokers who smoked greater than or equal to one pack per day (OR=0.80; 95% CI=0.24-2.67; p-interaction=0.08). No clear associations were observed for GSTT1 genotypes. CONCLUSIONS Risk of lung cancer increased as the number of deletion variants increased for GSTM1, although the associations were nonsignificant. Discriminating between the wild-type, hemizygous, and homozygous deletion GSTM1 genotypes permitted a more precise characterization of the associations between GSTM1 deletion variants and lung cancer.
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Affiliation(s)
- Tram Kim Lam
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Cancer Prevention Fellowship Program, Office of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Biostatistics, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Ingo Ruczinski
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Kathy Helzlsouer
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Mercy Medical Center, Baltimore, MD
- George W. Comstock Center for Public Health Research and Prevention, Hagerstown, MD
| | - Yin Yao Shugart
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | | | - Sandra Clipp
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- George W. Comstock Center for Public Health Research and Prevention, Hagerstown, MD
| | - Paul T. Strickland
- Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Anthony J. Alberg
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- George W. Comstock Center for Public Health Research and Prevention, Hagerstown, MD
- Hollings Cancer Center and Department of Biostatistics, Bioinformatics, and Epidemiology, Medical University of South Carolina, Charleston SC
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Bediaga NG, Alfonso-Sánchez MA, de Renobales M, Rocandio AM, Arroyo M, de Pancorbo MM. GSTT1 and GSTM1 gene copy number analysis in paraffin-embedded tissue using quantitative real-time PCR. Anal Biochem 2008; 378:221-223. [PMID: 18440293 DOI: 10.1016/j.ab.2008.04.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2008] [Revised: 04/02/2008] [Accepted: 04/04/2008] [Indexed: 01/10/2023]
Abstract
GSTT1 and GSTM1 genes possess an inherited deletion associated with a lack of enzyme activity. The heterozygous condition of this deletion is difficult to determine in low-quality DNA with existing PCR protocols. We designed and validated a multiplex real-time PCR assay by adapting the DeltaDeltaCt relative quantification method for the analysis of GSTT1 and GSTM1 markers to accurately differentiate the three genotypes ( *1/1, *1/0, and *0/0) in degraded DNA from formalin-fixed paraffin-embedded tissue. Gene copy number values obtained provide for unambiguous homozygous and heterozygous differentiation. The efficacy shown by the PCR assay endorses its usefulness for complete genotyping of glutathione S-transferases in archival tissues.
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Affiliation(s)
- Naiara G Bediaga
- Servicio de Genómica, Banco de ADN, Facultad de Farmacia, Universidad del País Vasco, 01006 Vitoria, Spain
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Al-Saleh I, Arif J, El-Doush I, Al-Sanea N, Jabbar AA, Billedo G, Shinwari N, Mashhour A, Mohamed G. Carcinogen DNA adducts and the risk of colon cancer: case-control study. Biomarkers 2008; 13:201-16. [PMID: 18270871 DOI: 10.1080/13547500701775449] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Colorectal cancer represents 8.5% of all tumours at the King Faisal Specialist Hospital & Research Centre. Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) have long been suspected to play a prominent role in colon cancer aetiology. We designed a case-control study to test the hypothesis of whether or not the presence of DNA adducts can play a role in the aetiology of colon cancer. DNA adducts were measured in 24 cancerous and 20 non-cancerous tissue samples of newly diagnosed colon cancer patients by (32)P-post-labelling technique. Normal tissue from 19 hospital patients served as controls. The mean levels of adducts per 10(10) nucleotides in cancerous and non-cancerous tissue were 151.75+/-217.27 and 114.81+/-186.10, respectively; however, only adducts in cancerous tissue were significantly higher than controls (32.78+/-57.51 per 10(10) nucleotides) with p-values of 0.017. No BPDE-DNA adducts were found. No relationship was found between urinary cotinine as a marker of tobacco smoke and 1-hydroxypyrene as an indicator of an individual's internal dose of PAHs and DNA adducts. In a logistic regression model, only adducts in cancerous tissue were associated with the subsequent risk of colon cancer, with an odds ratio of 3.587 (95% confidence interval 0.833-15.448) after adjustment for age and the duration of living in the current region, but of a borderline significance (p=0.086). Although it is difficult to arrive at a definite conclusion from a small dataset, our preliminary results suggest the potential role of DNA adducts in the colon carcinogenesis process. Additional studies with larger sample sizes are needed to confirm our preliminary finding. It is also important to identify the structural characterization of these unknown DNA adducts in order to have a better understanding of whether or not environmental carcinogens play a role in the aetiology of colon cancer.
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Affiliation(s)
- I Al-Saleh
- Biological & Medical Research Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
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Wang S, Chanock S, Tang D, Li Z, Jedrychowski W, Perera FP. Assessment of interactions between PAH exposure and genetic polymorphisms on PAH-DNA adducts in African American, Dominican, and Caucasian mothers and newborns. Cancer Epidemiol Biomarkers Prev 2008; 17:405-13. [PMID: 18268125 PMCID: PMC3171162 DOI: 10.1158/1055-9965.epi-07-0695] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Polycyclic aromatic hydrocarbons (PAH) are widespread pollutants commonly found in air, food, and drinking water. Benzo[a]pyrene is a well-studied representative PAH found in air from fossil fuel combustion and a transplacental carcinogen experimentally. PAHs bind covalently to DNA to form DNA adducts, an indicator of DNA damage, and an informative biomarker of potential cancer risk. Associations between PAH-DNA adduct levels and both cancer risk and developmental deficits have been seen in previous experimental and epidemiologic studies. Several genes have been shown to play an important role in the metabolic activation or detoxification of PAHs, including the cytochrome P450 genes CYP1A1 and CYP1B1 and the glutathione S-transferase (GST) genes GSTM1, and GSTT2. Genetic variation in these genes could influence susceptibility to adverse effects of PAHs in polluted air. Here, we have explored interactions between prenatal PAH exposure and 17 polymorphisms in these genes (rs2198843, rs1456432, rs4646903, rs4646421, rs2606345, rs7495708, rs2472299, rs162549, rs1056837, rs1056836, rs162560, rs10012, rs2617266, rs2719, rs1622002, rs140194, and gene deletion GSTM1-02) and haplotypes on PAH-DNA adducts in cord blood of 547 newborns and in maternal blood of 806 mothers from three different self-described ethnic groups: African Americans, Dominicans, and Caucasians. PAHs were measured by personal air monitoring of mothers during pregnancy. Significant interactions (p < 0.05) were observed between certain genetic polymorphisms and CYP1A1 haplotype and PAHs in mothers and their newborns in the three ethnic groups. However, with our limited sample size, the current findings are suggestive only, warranting further study.
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Affiliation(s)
- Shuang Wang
- Department of Biostatistics, Columbia University, New York, New York
| | | | - Deliang Tang
- Columbia Center for Children’s Environmental Health, Mailman School of Public Health, Columbia University, New York, New York
| | - Zhigang Li
- Department of Biostatistics, Columbia University, New York, New York
| | - Wieslaw Jedrychowski
- Columbia Center for Children’s Environmental Health, Mailman School of Public Health, Columbia University, New York, New York
| | - Frederica P. Perera
- Columbia Center for Children’s Environmental Health, Mailman School of Public Health, Columbia University, New York, New York
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Zhao H, Lin J, Grossman HB, Hernandez LM, Dinney CP, Wu X. Dietary isothiocyanates, GSTM1, GSTT1, NAT2 polymorphisms and bladder cancer risk. Int J Cancer 2007; 120:2208-13. [PMID: 17290402 DOI: 10.1002/ijc.22549] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Isothiocyanates (ITCs) are nonnutrient compounds in cruciferous vegetables with anticarcinogenic properties. ITCs down-regulate cytochrome P-450 biotransformation enzyme levels, activate Phase II detoxifying enzymes and induce apoptosis. On the other hand, ITCs also serve as a substrate for GSTs. Experimental evidences suggest that ITCs have anticarcinogenic effect on bladder cancer. Therefore, we evaluated dietary intake of ITCs, GSTM1, GSTT1 and NAT2 polymorphisms, and bladder cancer risk in a case-control study. There were 697 newly diagnosed bladder cancer cases identified from The University of Texas M. D. Anderson Cancer Center and 708 healthy controls matched to cases by age (+/-5), gender and ethnicity. Participants underwent an in-person interview, in which epidemiologic and food frequency questionnaires were administered to collect demographic and dietary intake data. Median ITC intake per day was statistically significantly lower in cases than in controls (0.23 vs. 0.33, p < 0.001). High ITC intake was associated with 29% decreased risk of bladder cancer [Odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.57, 0.89]. The protective effect was more evident in older individuals (> or =64-years-old), men, ever smokers and heavy smokers in stratified analysis. Compared with NAT2 rapid acetylator, NAT2 slow acetylator had an increased risk of bladder cancer in Caucasians (OR = 1.31, 95% CI = 1.02, 1.69). There was no main effect associated with the GSTM1 or GSTT1 genotypes. The protective effect of ITCs against bladder cancer was not modified by GSTM1, GSTT1 or NAT2 genotypes. This is the first epidemiological report that ITCs from cruciferous vegetable consumption protect against bladder cancer.
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Affiliation(s)
- Hua Zhao
- Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, 1155 Hermann Pressler Boulevard, Houston, TX 77030, USA
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Jiao L, Bondy ML, Hassan MM, Chang DZ, Abbruzzese JL, Evans DB, Smolensky MH, Li D. Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer. Cancer 2007; 109:840-8. [PMID: 17265526 PMCID: PMC1892189 DOI: 10.1002/cncr.22468] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Pancreatic cancer is a multifactorial disease with metastasis-prone and therapy-resistant nature. The authors hypothesized that genetic variants of glutathione S-transferase (GST) affect detoxification of carcinogens and anticancer agents in the human pancreas and, thus, the risk and survival of pancreatic cancer. METHODS Genotypes of GSTM1, GSTT1, and GSTP1 were determined in 352 patients with pancreatic ductal adenocarcinoma and in a control group of 315 healthy, non-Hispanic whites (frequency-matched by age and sex). Survival analysis was performed in a subset of 290 patients. Epidemiological and clinical information was obtained. A multiple unconditional logistic regression model, a Cox proportional hazards model, and log-rank tests were used for statistical analysis. RESULTS No significant main effects of any of 3 GST genes on the risk of pancreatic cancer were observed. Subgroup analysis showed that older individuals (aged >or=62 years) who carried the GSTP1*C ((105)Val-(114)Val) containing genotype tended to have a reduced risk compared with younger individuals who carried the non-*C genotype (for sex and pack-years of smoking, the adjusted odd ratio was 0.54; 95% confidence interval [95% CI], 0.29-1.02). In a survival analysis of 138 patients who received 5-flurorouracil, patients who carried the GSTP1*C containing genotype had a significantly longer survival than patients who carried the non-*C genotype (multivariate hazard ratio, 0.45; 95% CI, 0.22-0.94). CONCLUSIONS The GSTP1*C variant conferred a possible protective effect against pancreatic cancer in older individuals and a significant survival advantage in patients who received 5-florouracil. The current findings must be confirmed before further inferences can be made.
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Affiliation(s)
- Li Jiao
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Melissa L. Bondy
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Manal M. Hassan
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - David Z. Chang
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - James L. Abbruzzese
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Douglas B. Evans
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Michael H. Smolensky
- Division of Environmental and Occupational Health, The University of Texas School of Public Health, Houston, Texas
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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Sørensen M, Raaschou-Nielsen O, Brasch-Andersen C, Tjønneland A, Overvad K, Autrup H. Interactions between GSTM1, GSTT1 and GSTP1 polymorphisms and smoking and intake of fruit and vegetables in relation to lung cancer. Lung Cancer 2006; 55:137-44. [PMID: 17123660 DOI: 10.1016/j.lungcan.2006.10.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Revised: 10/06/2006] [Accepted: 10/15/2006] [Indexed: 11/18/2022]
Abstract
Polymorphisms in glutathione S-transferases (GST) are weakly associated with risk for lung cancer. We examined gene-environment interactions in relation to lung cancer in 430 cases and 767 comparison persons identified within a prospective cohort of 57,053 persons. We used assays capable of discriminating heterozygous individuals from those with two functional alleles and homozygous deletions in GSTM1 and GSTT1. There was no overall association between the GST polymorphisms and lung cancer. We found that fruit and vegetables reduced the risk of lung cancer only among carriers of at least one functional GSTM1 allele, and among carriers of two GSTP1 Val alleles. There were no significant interactions between the GST polymorphisms and smoking.
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Affiliation(s)
- Mette Sørensen
- Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, 2100 Copenhagen Ø, Denmark.
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Ji BT, Weissfeld JL, Chow WH, Huang WY, Schoen RE, Hayes RB. Tobacco smoking and colorectal hyperplastic and adenomatous polyps. Cancer Epidemiol Biomarkers Prev 2006; 15:897-901. [PMID: 16702367 DOI: 10.1158/1055-9965.epi-05-0883] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal adenomas and possibly some hyperplastic polyps are precursors of colorectal cancer. Tobacco use is associated in epidemiologic studies with these polyps, although links between smoking and colorectal cancer are less consistent. To characterize the role of tobacco in early colorectal carcinogenesis, we compared tobacco use among 4,383 subjects with histologically verified benign (hyperplastic or adenomatous) polyps of the distal colon (descending colon, sigmoid, and rectum) with tobacco use among 33,667 subjects who were endoscopy negative for distal colon tumors, in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Trial, a randomized trial of flexible sigmoidoscopy. Risks, estimated by the odds ratio (OR), associated with current cigarette use were OR = 4.4 [95% confidence interval (95% CI), 3.7-5.2] for hyperplastic polyps only, OR = 1.8 (95% CI, 1.5-2.1) for adenomas only, and OR = 6.2 (95% CI, 4.7-8.3) for subjects with both hyperplastic and adenomatous polyps concurrently. Effects were weaker among ex smokers; the smoking-associated ORs remained consistently higher for hyperplastic polyps. This pattern was also seen in relation to cigarettes smoked per day, smoking duration, and pack-years. Tobacco-associated risks for multiple polyps were also stronger when hyperplastic disease was involved. In conclusion, tobacco use, particularly recent use, increases risk for both adenomatous and hyperplastic polyps, but the risks are substantially greater for hyperplastic lesions.
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Affiliation(s)
- Bu-Tian Ji
- National Cancer Institute, 6120 Executive Boulevard, EPS 8120, Bethesda, MD 20852, USA.
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Huang WY, Berndt SI, Kang D, Chatterjee N, Chanock SJ, Yeager M, Welch R, Bresalier RS, Weissfeld JL, Hayes RB. Nucleotide excision repair gene polymorphisms and risk of advanced colorectal adenoma: XPC polymorphisms modify smoking-related risk. Cancer Epidemiol Biomarkers Prev 2006; 15:306-11. [PMID: 16492920 DOI: 10.1158/1055-9965.epi-05-0751] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES Nucleotide excision repair enzymes remove bulky damage caused by environmental agents, including carcinogenic polycyclic aromatic hydrocarbons found in cigarette smoke, a risk factor for colorectal adenoma. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we studied the risk of advanced colorectal adenoma in relation to cigarette smoking and selected single nucleotide polymorphisms (SNP) in the nucleotide excision repair pathway. METHODS Cases (n = 772) were subjects with left-sided advanced adenoma (>1 cm in size, high-grade dysplasia, or villous characteristics). Controls (n = 777) were screen-negative for left-sided polyps by sigmoidoscopy. DNA was extracted from blood samples and 15 common nonsynonymous SNPs in seven-nucleotide excision repair genes [XPC, RAD23B (hHR23B), CSB (ERCC6), XPD (ERCC2), CCNH, XPF (ERCC4), and XPG (ERCC5)] were genotyped. RESULTS None of the studied SNPs were independently associated with advanced adenoma risk. Smoking was related to adenoma risk and XPC polymorphisms (R492H, A499V, K939Q) modified these effects (P(interaction) from 0.03-0.003). Although the three XPC variants were in linkage disequilibrium, a multivariate logistic regression tended to show independent protective effects for XPC 499V (P(trend) = 0.06), a finding supported by haplotype analysis (covariate-adjusted global permutation P = 0.03). CONCLUSIONS Examining a spectrum of polymorphic variants in nucleotide excision repair genes, we found evidence that smoking-associated risks for advanced colorectal adenoma are modified by polymorphisms in XPC, particularly haplotypes containing XPC 499V.
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Affiliation(s)
- Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, EPS 8113, MSC 7240, Bethesda, Maryland 20892, USA.
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Tijhuis MJ, Wark PA, Aarts JMMJG, Visker MHPW, Nagengast FM, Kok FJ, Kampman E. GSTP1 and GSTA1 polymorphisms interact with cruciferous vegetable intake in colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 2006; 14:2943-51. [PMID: 16365014 DOI: 10.1158/1055-9965.epi-05-0591] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The possible interplay between cruciferous vegetable consumption, functional genetic variations in glutathione S-transferases (GST) M1, T1, P1, and A1, and colorectal adenomas, was investigated in a Dutch case-control study. The GSTM1 and GSTT1 deletion polymorphisms, and the single nucleotide polymorphisms in GSTP1 (A313G) and in GSTA1 (C-69T) were assessed among 746 cases who developed colorectal adenomas and 698 endoscopy-based controls without any type of colorectal polyps. High and low cruciferous vegetable consumption was defined based on a median split in the control group. High consumption was slightly positively associated with colorectal adenomas [odds ratio (OR) 1.15; 95% confidence interval, 0.92-1.44]. For GSTP1, a positive association with higher cruciferous vegetable intake was only apparent in individuals with the low-activity GSTP1 genotype (GG genotype, OR 1.94; 95% confidence interval, 1.02-3.69). This interaction was more pronounced in men, with higher age and with higher meat intake. The GSTA1 polymorphism may have a modifying role as well: the OR for higher intake compared with lower intake was 1.57 (0.93-2.65) for individuals homozygous for the low expression variant (TT genotype). This seemed to be stronger with younger age and higher red meat intake. Cruciferous vegetable consumption and the combined GSTA1 and GSTP1 genotypes showed a statistically significant interaction (P = 0.034). The GSTM1 and GSTT1 genotypes did not seem to modify the association between cruciferous vegetable intake and colorectal adenomas. In conclusion, GSTP1 and GSTA1 genotypes might modulate the association between cruciferous vegetable intake and colorectal adenomas.
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Affiliation(s)
- Mariken J Tijhuis
- Division of Human Nutrition, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, the Netherlands
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Gal TJ, Huang WY, Chen C, Hayes RB, Schwartz SM. DNA repair gene polymorphisms and risk of second primary neoplasms and mortality in oral cancer patients. Laryngoscope 2006; 115:2221-31. [PMID: 16369171 DOI: 10.1097/01.mlg.0000183736.96004.f7] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES/HYPOTHESIS We tested the hypothesis that polymorphisms in genes involved in DNA repair pathways are associated with the development of second primary neoplasms of the upper aerodigestive tract (UADT), as well as mortality, in patients previously diagnosed with oral squamous cell cancer (OSCC). METHODS DNA specimens from 279 OSCC patients who had participated in two previous population-based case-control studies were assayed for the following polymorphisms: X-ray repair cross-complementing (XRCC) 1 Arg399Gln, XRCC3 Thr241Met, xeroderma pigmentosum complementing group D (XPD) Lys751Gln, and O-methylguanine- DNA methyltransferase (MGMT) Leu84Phe and Val143Ile. Baseline demographic information was obtained from personal interviews and tumor characteristics and treatment were obtained from cancer registry files. Cox proportional hazards models were used to calculate hazards ratio (HR) estimates for each polymorphism in relation to the risk of developing second primary neoplasms at any site, UADT, and head and neck. HRs were also determined for associations with all-cause mortality and oral cancer specific mortality. RESULTS A significant increased risk of second neoplasms (all sites combined, as well as for UADT sites and for head and neck squamous cell cancers) was observed among XRCC3 241Met allele homozygotes (HR 2.65-3.44, P < .02). No significant association with the development of second neoplasms was observed for the XRCC1 399Gln, XPD 751Gln, or MGMT 84Phe or 143Ile alleles. Although no associations with oral cancer-specific mortality were observed, we found a significant inverse association between all-cause mortality and possessing at least one copy of the XRCC1 399Gln allele (HR 0.68, 95% confidence interval [CI] 0.47-0.97, P = .03), as well as a suggestion of a direct association between all-cause mortality and having one copy of the XRCC3 241Met allele (HR 1.39, 95% CI 0.95-2.03, P = .09). CONCLUSIONS Polymorphisms in the DNA repair enzyme gene XRCC3 241Met was associated with an increased risk of second neoplasms, and polymorphisms of the XRCC1 399Gln gene were associated with a decreased risk of all-cause mortality in patients with primary OSCC. These findings require confirmation in other populations before the clinical implications can be considered.
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Affiliation(s)
- Thomas J Gal
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Washington, Seattle, Washington 98195, USA.
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