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Karimi-Zarchi M, Moghimi M, Abbasi H, Hadadan A, Salimi E, Morovati-Sharifabad M, Akbarian-Bafghi MJ, Zare-Shehneh M, Mosavi-Jarrahi A, Neamatzadeh H. Association of MTHFR 677C>T Polymorphism with Susceptibility to Ovarian and Cervical Cancers: A Systematic Review and Meta-Analysis. Asian Pac J Cancer Prev 2019; 20:2569-2577. [PMID: 31554347 PMCID: PMC6976840 DOI: 10.31557/apjcp.2019.20.9.2569] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Indexed: 12/14/2022] Open
Abstract
Background: Previous studies have evaluated the impact of MTHFR 677C>T polymorphism on susceptibility to ovarian and cervical cancers in women, but the conclusions are still controversial. To get a more precise evaluation of the association between MTHFR 677C>T polymorphism and risk of ovarian and cervical cancers, we performed a meta-analysis of the association of all eligible studies. Methods: A comprehensive search performed in PubMed, Google Scholar, CNKI, and Web of Science databases to identify the relevant studies up to October 15, 2018. The strength of the association was estimated by odds ratios (OR) with 95% confidence interval (CI). Results: A total of 27 case-control studies including eleven studies with 4990 cases 7730 controls on ovarian cancer and 16 studies with 4990 cases and 7730 controls on cervical cancer were selected. Pooled data revealed that the MTHFR 677C>T polymorphism not significantly associated with an increased risk of ovarian and cervical cancers under all five genetic models. However, stratified analysis by ethnicity showed that the MTHFR 677C>T polymorphism was significantly associated with risk of ovarian cancer in Asians. No publication bias was found in the current meta-analysis. Conclusions: The results of this meta-analysis proposes that the MTHFR 677C>T polymorphism may not play a role in development of ovarian and cervical cancers in overall population. Further well-designed studies are necessary to clarify the precise role of the MTHFR 677C>T polymorphism on ovarian and cervical cancers risk.
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Affiliation(s)
- Mojgan Karimi-Zarchi
- Department of Gynecology and Obstetrics, Iran University of Medical Sciences, Tehran, Iran
| | - Mansour Moghimi
- Department of Pathology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Hajar Abbasi
- Department of Gynecology and Obstetrics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amaneh Hadadan
- Department of Gynecology and Obstetrics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Erfaneh Salimi
- Department of Gynecology and Obstetrics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Masoud Zare-Shehneh
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alireza Mosavi-Jarrahi
- Department of Social Medicine, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Neamatzadeh
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Hajiesmaeil M, Tafvizi F, Sarmadi S. The effect of methylenetetrahydrofolate reductase polymorphisms on susceptibility to human papilloma virus infection and cervical cancer. INFECTION GENETICS AND EVOLUTION 2016; 46:1-6. [DOI: 10.1016/j.meegid.2016.10.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 10/13/2016] [Accepted: 10/17/2016] [Indexed: 02/02/2023]
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The association between MTHFR polymorphisms and cervical cancer risk: a system review and meta analysis. Arch Gynecol Obstet 2016; 294:579-88. [PMID: 26879954 DOI: 10.1007/s00404-016-4037-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 02/03/2016] [Indexed: 12/28/2022]
Abstract
PURPOSE Methylenetetrahydrofolate reductase (MTHFR) plays an important role in determining the proportions of folate coenzymes for DNA synthesis or DNA methylation. Published data on the association between the MTHFR polymorphisms and cervical risk are controversial. A meta-analysis was performed to assess whether the polymorphisms of MTHFR are associated with cervical cancer risk. METHODS Medline, Embase, China National Knowledge Infrastructure and Chinese Biomedicine Databases were searched to identify eligible studies. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) for MTHFR C677T and MTHFR A1298C polymorphisms and cervical cancer were appropriately derived from fixed-effects or random effects models. Five different ORs were calculated: (1) allele contrast (C vs. T), (2) homozygous comparison (CC vs. TT), (3) heterozygous comparison (CC vs. CT), (4) dominant model (CC vs. CT+TT) and (5) recessive model (CC+CT vs. TT). RESULTS A total of 13 studies, which included 12 studies for MTHFR C677T (2332 cases and 3000 controls) and five studies for A1298C polymorphisms (677 cases and 1191 controls), were enrolled in this meta-analysis. The pooled analyses revealed that MTHFR C677T polymorphism was not associated with cervical cancer risk; while the A1298C polymorphism had a significant association with increased cervical cancer risk in allele contrast, heterozygote comparison and dominant model (A C, OR = 0.84, 95 % CI = 0.71-0.98; AA vs. CC OR = 0.72, 95 % CI = 0.59-0.89; AA vs. AC+CC, OR = 0.72, 95 % CI = 0.59-0.88). The significant associations between MTHFR A1298C polymorphism and cervical cancer were found among Asians and population-based case-control studies. CONCLUSIONS This study indicated that the MTHFR C677T may be no associated with cervical cancer risk, and yet the MTHFR A1298C polymorphism may be a risk factor for cervical cancer.
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Badiga S, Johanning GL, Macaluso M, Azuero A, Chambers MM, Siddiqui NR, Piyathilake CJ. A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era. PLoS One 2014; 9:e110093. [PMID: 25302494 PMCID: PMC4193871 DOI: 10.1371/journal.pone.0110093] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 09/15/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. METHODS The study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. RESULTS The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017). CONCLUSIONS This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation.
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Affiliation(s)
- Suguna Badiga
- The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Gary L. Johanning
- Biosciences Division, Center for Cancer and Metabolism, SRI International, Menlo Park, California, United States of America
| | - Maurizio Macaluso
- The Department of Pediatrics, Division of Biostatistics and Epidemiology, The University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Andres Azuero
- The Department of Community Health Outcomes and System, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Michelle M. Chambers
- The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Nuzhat R. Siddiqui
- The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Chandrika J. Piyathilake
- The Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- * E-mail:
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MTHFR/p53 Polymorphisms as Genetic Factors for Cervical Intraepithelial Neoplasia and Cervical Cancer in HPV-infected Mexican Women. Int J Biol Markers 2014; 29:e142-9. [DOI: 10.5301/jbm.5000070] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2013] [Indexed: 02/04/2023]
Abstract
We performed a case-control association study to evaluate the association between common polymorphisms in MTHFR (C677T and A1298C) and the Arg72Pro polymorphism in the p53 gene and the risk for cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC) in Mexican HPV-infected women. We included 131 women with diagnosis of CIN grade I-II and 78 with CIN III or ICC; as controls we also included 274 women with normal Pap smear and negative HPV test. Genotyping for MTHFR and p53 polymorphisms was performed by PCR-RFPLs. HPV was tested by Hybrid Capture II. Odds ratios and 95% confidence intervals were estimated. Genotype frequencies for the 3 studied polymorphisms were distributed according to the Hardy-Weinberg equilibrium. The A1298C-MTHFR polymorphism showed significant differences for the heterozygous AC genotype and the C allele, whereas the AA genotype and A allele resulted to be genetic risk factors for CIN or ICC (p<0.03). The Arg72Pro-p53 polymorphism showed for the genotypes Arg/Pro and Pro/Pro, and for the Pro allele, a significant association only to the risk for CIN (p<0.03). The MTHFR/p53 interaction showed that the genotype combinations AA/ArgArg and AA/ArgPro were associated, respectively, to the risk of ICC and CIN (p<0.05). This study suggests that the A1298C-MTHFR polymorphism contributes to the genetic risk for both CIN and ICC, whereas the Arg72Pro-p53 polymorphism only contributes to the risk for CIN. The MTHFR/p53 genetic combinations AA/ArgArg and AA/ArgPro are associated genetic risk factors for ICC and CIN in Mexican HPV-infected women.
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Thrombophilic Genetic Factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A in Noncirrhotic Portal Vein Thrombosis and Budd-Chiari Syndrome in a Caucasian Population. Int J Vasc Med 2013; 2013:717480. [PMID: 24455271 PMCID: PMC3880691 DOI: 10.1155/2013/717480] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 09/15/2013] [Accepted: 09/30/2013] [Indexed: 12/28/2022] Open
Abstract
Thrombophilic genetic factors PAI-1, MTHFRC677T, V Leiden 506Q, and Prothrombin 20210A were studied as risk factors in 235 Caucasian subjects: 85 patients with abdominal thrombosis (54 with portal vein thrombosis (PVT) and 31 with Budd-Chiari syndrome (BCS) without liver cirrhosis or hepatocellular carcinoma) and 150 blood bank donors. Seventy-five patients with PVT/BCS showed associated disease or particular clinical status (46 PVT/29 BCS): 37 myeloproliferative neoplasm (20 PVT/17 BCS), 12 abdominal surgery (10 PVT/2 BCS), 10 contraception or pregnancy (6 PVT/4 BCS), 7 abdominal acute disease (6 PVT/1 BCS), and 9 chronic disease (4 PVT/5 BCS); ten patients did not present any association (8 PVT/2 BCS). PAI-14G-4G, MTHFR677TT, and V Leiden 506Q were significantly frequent (OR 95% CI and χ2 test with P value) in abdominal thrombosis; in these patients PAI-14G-4G and MTHFR677TT distributions deviated from that expected from a population in the Hardy-Weinberg equilibrium (PAI-1: χ2 = 13.8, P < 0.001; MTHFR677: χ2 = 7.1, P < 0.01), whereas the equilibrium was respected in healthy controls. V Leiden Q506 and Prothrombin 20210A were in the Hardy-Weinberg equilibrium both in patients with abdominal thrombosis and healthy controls. Our study shows an important role of PAI-14G-4G and MTHFR677TT in abdominal thrombosis without liver cirrhosis or hepatocellular carcinoma.
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Wu CY, Yang M, Lin M, Li LP, Wen XZ. MTHFR C677T polymorphism was an ethnicity-dependent risk factor for cervical cancer development: evidence based on a meta-analysis. Arch Gynecol Obstet 2013; 288:595-605. [PMID: 23463325 DOI: 10.1007/s00404-013-2721-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 01/15/2013] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Many studies have studied the associations between 5, 10-methylene tetrahydrofolate reductase (MTHFR) polymorphisms and susceptibilities of cervical cancer and cervical intraepithelial neoplasia (CIN); however, the results were inconsistent. The aim of this study was to further assess the relationships by the method of meta-analysis. MATERIALS AND METHODS Two investigators independently searched the PubMed, Embase, Wang Fang (Chinese database) and CNKI (China National Knowledge Infrastructure), with latest update to July 1st, 2011. The pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were used to assess the strength of the associations by using fixed- or random-effect model. RESULTS Ten case-control studies were included in this meta-analysis including a total of 1,803 cervical cancer or CIN cases and 2,363 controls. Pooled analyses showed that T allele of MTHFR C677T was significantly associated with increased CIN risk [OR (95 % CI): 1.28 (1.03-1.50) for CT vs. CC], especially for low-grade CIN risk. In addition, MTHFR C677T rather than A1298C polymorphism was associated with risk of cervical cancer. Stratifying analyses for ethnicity indicated that T allele of MTHFR C677T was associated with increased cervical cancer risk for Asian [OR (95 % CI): 1.56 (1.17-2.08) for TT vs. CC; 1.53 (1.19-1.96) for TT vs. C carriers] while decreased risk for Caucasian [OR (95 % CI): 0.63 (0.45-0.89) for TT vs. CC; 0.66 (0.56-0.79) for T carriers vs. CC]. CONCLUSION This meta-analysis suggested that there was no association between MTHFR A1298C polymorphism and cervical cancer risk. However, MTHFR C677T was an ethnicity-dependent risk factor for cervical cancer occurrence. In addition, T allele of C677T was significantly associated with risk of low grade of CIN incidence. Because of modest limitations of our study, well-designed studies with large sample size were needed to confirm our findings in the future.
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Affiliation(s)
- Cheng Yong Wu
- Department of Obstetrics and Gynecology, Meizhou People's Hospital, Meizhou, Gaungzhou, China
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Zhu J, Wu L, Kohlmeier M, Ye F, Cai W. Association between MTHFR C677T, MTHFR A1298C and MS A2756G polymorphisms and risk of cervical intraepithelial neoplasia II/III and cervical cancer: a meta-analysis. Mol Med Rep 2013; 8:919-27. [PMID: 23864153 DOI: 10.3892/mmr.2013.1589] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 06/17/2013] [Indexed: 11/06/2022] Open
Abstract
Numerous case-control studies on the association between polymorphisms of key genes involved in methionine remethylation [methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS)] and the susceptibility of cervical intraepithelial neoplasia (CIN) and cervical cancer have provided inconclusive results. The aim of the present meta-analysis was to determine the effects of two MTHFR (C677T and A1298C) and one MS gene polymorphism (A2756G) on the risk of CIN II/III or cervical cancer. Relevant data were retrieved following a systematic search in PubMed, Web of Science, MEDLINE and Wanfang Data up to November 2012. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated from eligible studies by meta-analysis with subgroup analyses stratified by ethnicity. A total of 13 studies with 1,936 cases and 2,858 controls were included in the present meta‑analysis. An increased risk of cervical cancer was found in Asian women with the MTHFR 677T allele (TT vs. CC: OR=1.41, 95% CI=1.07‑1.86, P=0.01; TT vs. CC+CT: OR=1.38, 95% CI=1.08-1.75, P=0.008), while a decreased risk was observed in Caucasian women (TT vs. CC: OR=0.65, 95% CI=0.45-0.93, P=0.02; TT+CT vs. CC: OR=0.7, 95% CI=0.58-0.86, P=0.0005). No effects of MTHFR C677T polymorphism on CIN II/III risk and MTHFR A1298C or MS A2756G polymorphisms on cervical cancer risk were detected. The sensitivity analysis suggested stability of this meta-analysis and no publication bias was detected. The MTHFR 677T allele may enhance the risk of cervical cancer in the Asian female population and play a protective role in Caucasian females. However, limited association is suggested between MTHFR A1298C and MS A2756G polymorphisms with cervical tumorigenesis.
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Affiliation(s)
- Jie Zhu
- Xin Hua Hospital, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
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Chen H, Zhu J. C677T polymorphism of methylenetetrahydrofolate reductase may contribute to cervical cancer risk in complete over-dominant model. Med Hypotheses 2013; 80:679-83. [PMID: 23490201 DOI: 10.1016/j.mehy.2013.01.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/18/2013] [Accepted: 01/24/2013] [Indexed: 01/08/2023]
Abstract
PURPOSE Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate. The single nucleotide polymorphism (SNP), C677T (Ala>Val, rs1801133), has been confirmed to decrease the enzyme activity. The association between C677T and cervical cancer susceptibility has been widely studied. However, the results were inconsistent. In order to elucidate the role of this SNP in cervical cancer, a meta-analysis was conducted. METHODS The literature search was performed using the following databases: PubMed, Embase and ISI Web of Science up to December 2012. The effect of association was indicated as crude odds ratio (OR) with the corresponding 95% confidence interval (CI). RESULTS Six studies including 1431 cases and 1915 controls explored C677T genotypes were involved in this meta-analysis. Overall meta-analysis showed that C677T polymorphism increased cervical cancer risk in the complete over-dominant model (random-effect OR=1.33, 95% CI: 1.00-1.77, I(2)=69%). After excluding one study which showed apparent heterogeneity, the heterogeneity disappeared. The meta-analysis of five studies including 1231 cases and 1715 controls showed the fixed-effect OR reached 1.20 (95% CI: 1.03-1.40, I(2)=0) as (TT+CC) in the complete over-dominant model. CONCLUSIONS C677T polymorphism of MTHFR gene may increase the risk of cervical cancer in the complete over-dominant model. The association merits replicating and validating in further studies.
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Affiliation(s)
- Hongmei Chen
- Department of Gynaecology, Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, China
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Yu L, Chang K, Han J, Deng S, Chen M. Association between Methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to cervical cancer: a meta-analysis. PLoS One 2013; 8:e55835. [PMID: 23431363 PMCID: PMC3576378 DOI: 10.1371/journal.pone.0055835] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 01/02/2013] [Indexed: 01/11/2023] Open
Abstract
Background To assess the association between MTHFR polymorphism and cervical cancer risk, a meta-analysis was performed. Methods Based on comprehensive searches of the PubMed, Embase, and Web of Science databases, we identified outcome data from all articles estimating the association between MTHFR polymorphism and cervical cancer risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Results A total of 12 studies with 2,924 cases (331 cervical intraepithelial neoplasia (CIN) I, 742 CIN II/III, 1851 invasive cervical cancer) and 2,581 controls were identified. There was no significant association between MTHFR C677T polymorphism and CIN I risk (T vs. C, OR = 1.10, 95% CI = 0.92–1.31; TT vs. CC, OR = 1.14, 95% CI = 0.78–1.68; TT+CT vs. CC, OR = 1.22, 95% CI = 0.94–1.58; TT vs. CT+CC, OR = 0.99, 95% CI = 0.70–1.40). For the CIN II/III, lack of an association was also found (T vs. C, OR = 1.08, 95% CI = 0.95–1.23; TT vs. CC, OR = 1.15, 95% CI = 0.87–1.52; TT+CT vs. CC, OR = 1.13, 95% CI = 0.94–1.35; TT vs. CT+CC, OR = 1.07, 95% CI = 0.83–1.38). The T allele had significant association to susceptibility of invasive cervical cancer in recessive model (TT vs. CT+CC, OR = 1.23, 95% CI = 1.02–1.49). On subgroup analysis by ethnicity, similarly significant differences in T vs. C, TT vs. CC, and recessive model were found in Asians. Conclusion The present meta-analysis suggested that MTHFR C677T polymorphism were to substantially contribute to invasive cervical cancer in recessive model.
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Affiliation(s)
- Lili Yu
- Department of Obstetrics and Gynecology, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Kai Chang
- Department of Laboratory Medicine, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Jian Han
- Department of Obstetrics and Gynecology, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Shaoli Deng
- Department of Laboratory Medicine, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing, China
- * E-mail: (MC); (SD)
| | - Ming Chen
- Department of Laboratory Medicine, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing, China
- * E-mail: (MC); (SD)
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Wu XY, Ni J, Xu WJ, Zhou T, Wang X. Interactions between MTHFR C677T-A1298C variants and folic acid deficiency affect breast cancer risk in a Chinese population. Asian Pac J Cancer Prev 2013; 13:2199-206. [PMID: 22901194 DOI: 10.7314/apjcp.2012.13.5.2199] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Our objective was to evaluate the MTHFR C677T-A1298C polymorphisms in patients with breast cancer and in individuals with no history of cancer, to compare the levels of genetic damage and apoptosis under folic acid (FA) deficiency between patients and controls, and to assess associations with breast cancer. METHODS Genetic damage was marked by micronucleated binucleated cells (MNBN) and apoptosis was estimated by cytokinesis-block micronucleus assay (CBMN). PCR-RFLP molecular analysis was carried out. RESULTS The results showed significant associations between the MTHFR 677TT or the combined MTHFR C677T-A1298C and breast cancer risk (OR=2.51, CI=0.85 to 7.37, p=0.08; OR=4.11, CI=0.78 to 21.8, p<0.001). The MNBN from the combined MTHFR C677T-A1298C was higher and the apoptosis was lower than that of the single variants (p<0.05). At 15 to 60 nmol /L FA, the MNBN in cases with the TTAC genotype was higher than controls (p<0.05), whereas no significant difference in apoptosis was found between the cases and controls after excluding the genetic background. CONCLUSIONS Associations between the combined MTHFR C677T-A1298C polymorphism and breast cancer are possible from this study. A dose of 120 nmol/L FA could enhance apoptosis in cases with MTHFR C677T-A1298C. Breast cancer individuals with the TTAC genotype may be more sensitive to the genotoxic effects of FA deficiency than controls.
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Affiliation(s)
- Xia-Yu Wu
- School of Life Sciences, Yunnan University, Kunming, China
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Long S, Yang X, Liu X, Yang P. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and susceptibility for cervical lesions: a meta-analysis. PLoS One 2012; 7:e52381. [PMID: 23285018 PMCID: PMC3528671 DOI: 10.1371/journal.pone.0052381] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 11/12/2012] [Indexed: 01/08/2023] Open
Abstract
Background The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis. Methods The previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping. Results Neither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P = 0.006, OR = 0.83, 95% CI = 0.72–0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69–1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53–1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P = 0.06, OR = 1.21, 95% CI = 0.99–1.49) and AC vs. AA (P = 0.09, OR = 1.21, 95% CI = 0.97–1.51). Conclusions The MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study.
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Affiliation(s)
- Shuyu Long
- Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xingliang Yang
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Xiaojiao Liu
- Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Pei Yang
- Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China
- * E-mail:
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Cervical cancer with polymorphism in MTHFR C677T gene: a systematic review and meta-analysis. Mol Biol Rep 2012; 40:255-62. [PMID: 23070908 DOI: 10.1007/s11033-012-2056-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 10/03/2012] [Indexed: 01/06/2023]
Abstract
To perform a meta-analysis investigating the association of MTHFR C677T polymorphism and susceptibility of cervical cancer. All case-control studies published in English and Chinese with estimates of the relationship between MTHFR C677T polymorphism and risk of cervical cancer were analyzed using odds ratio (OR) with 95 % confidence interval (CI). A total of 10 studies (2,023 cases and 2,570 controls) were included in the meta-analysis. No significant association was observed between T allele and C allele (OR = 0.90; 95 %CI = 0.70-1.17; P = 0.43), and for genotype TT versus CC (OR = 1.09; 95 %CI = 0.74-1.61; P = 0.67), CT versus CC (OR = 0.95; 95 %CI = 0.75-1.20; P = 0.65), CT + TT versus CC (OR = 0.91; 95 %CI = 0.66-1.24; P = 0.55). The current meta-analysis results suggest that the MTHFR C677T polymorphism may not be associated with cervical cancer.
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Chattopadhyay K. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer. INDIAN JOURNAL OF HUMAN GENETICS 2012; 17:132-44. [PMID: 22345983 PMCID: PMC3276980 DOI: 10.4103/0971-6866.92087] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals.
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Affiliation(s)
- Koushik Chattopadhyay
- Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, Republic of South Africa
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Luo YL, Ye P, Zhang QH, Hu TT, Luo MH, Li MQ, Chen Q. Methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia: a meta-analysis. PLoS One 2012; 7:e46272. [PMID: 23029458 PMCID: PMC3460879 DOI: 10.1371/journal.pone.0046272] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 08/28/2012] [Indexed: 12/14/2022] Open
Abstract
Background A number of studies have explored the association between methyl enetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia (CIN). However, results remained controversial. To address this gap, we decided to conduct a meta-analysis of all available published studies. Methods Electronic literature searches of the PubMed, EmBase and Medline databases were performed up to April 30, 2012. Fixed-effects or random-effects model was used to calculate the pooled ORs for different genetic models. Results A total of 12 case-control studies were ultimately identified. No statistical correlation was found between C677T variants and cervical cancer for the overall population. However, subgroup analyses on the White women pointed to a significant protective effect for individuals heterozygous or homozygous for the T-allele (for CT vs. CC: OR = 0.72, 95% CI 0.59–0.88; for TT vs. CC: OR = 0.69, 95% CI = 0.49–0.97; for CT+TT vs. CC: OR = 0.71, 95% CI 0.59–0.86). C677T variants were associated with neither combined nor stratified CIN among the overall population. Conclusions This meta-analysis suggests that White women with mutant C677T genotypes might have a lower risk of cervical cancer, yet lacking enough statistical robustness. Further investigations are needed to get more insight into the role of this polymorphism in cervical carcinogenesis.
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Affiliation(s)
| | | | | | | | | | | | - Qing Chen
- Department of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China
- * E-mail:
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MTHFR C677T and A1298C polymorphisms and cervical carcinoma susceptibility: meta-analyses based on 4421 individuals. Mol Biol Rep 2012; 39:8723-32. [DOI: 10.1007/s11033-012-1732-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 06/06/2012] [Indexed: 01/11/2023]
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17
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Guo LN. Methylenetetrahydrofolate Reductase C677T Polymorphism and Cervical Cancer Risk: a Meta-Analysis. Asian Pac J Cancer Prev 2012; 13:2193-7. [DOI: 10.7314/apjcp.2012.13.5.2193] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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18
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Folate and choline metabolism gene variants and development of uterine cervical carcinoma. Clin Biochem 2011; 44:596-600. [PMID: 21349258 DOI: 10.1016/j.clinbiochem.2011.02.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 12/10/2010] [Accepted: 02/09/2011] [Indexed: 11/21/2022]
Abstract
OBJECTIVE It has been reported that aberrant DNA methylation can be associated with HPV infection and cervical tumorigenesis. The aim of this study was to evaluate the possibility that polymorphic variants of genes that may affect DNA methylation status are associated with the risk of cervical cancer in the Polish population. DESIGN AND METHOD Employing PCR-RFLPs and HRM analyses, we examined the prevalence of BHMT Arg239Gln (rs3733890), MTR Asp919Gly (rs1805087), MTHFR Ala222Val (rs1801133), MTHFD1 Arg653Gln (rs2236225) and MTRR Ile22Met (rs1801394) genotypes and alleles in patients with advanced cervical cancer (n=124) and controls (n=168). RESULTS The odds ratio (OR) for BHMT Gln/Gln genotype was 0.433 (95% CI=0.1780-1.054; p=0.0602). The OR for patients having the BHMT Arg/Gln or Gln/Gln genotypes was 0.579 (95% CI=0.3622-0.924; p=0.0216). We also observed a significantly higher frequency of the BHMT 239Gln allele in controls than in patients, p=0.0165. The genotype and allele frequencies of the MTR Asp919Gly, MTHFR Ala222Val, MTHFD1 Arg653Gln and MTRR Ile22Met gene variants did not display statistical differences between patients with cervical cancer and controls. We also did not find a significant association between the distribution of any genotypes or alleles and cancer characteristics. CONCLUSION Our results might suggest the protective role of the BHMT 239Gln variant in cervical cancer incidence.
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Common polymorphisms in methylenetetrahydrofolate reductase gene are associated with risks of cervical intraepithelial neoplasia and cervical cancer in women with low serum folate and vitamin B12. Cancer Causes Control 2010; 22:63-72. [DOI: 10.1007/s10552-010-9675-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2009] [Accepted: 10/18/2010] [Indexed: 12/31/2022]
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20
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Kohaar I, Kumar J, Thakur N, Hussain S, Niyaz MK, Das BC, Sengupta S, Bharadwaj M. Homocysteine levels are associated with cervical cancer independent of methylene tetrahydrofolate reductase gene (MTHFR) polymorphisms in Indian population. Biomarkers 2010; 15:61-8. [DOI: 10.3109/13547500903295881] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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21
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Agodi A, Barchitta M, Cipresso R, Marzagalli R, La Rosa N, Caruso M, Castiglione MG, Travali S. Distribution of p53, GST, and MTHFR Polymorphisms and Risk of Cervical Intraepithelial Lesions in Sicily. Int J Gynecol Cancer 2010; 20:141-6. [DOI: 10.1111/igc.0b013e3181c20842] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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22
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Singh H, Jain M, Sachan R, Mittal B. Association of TNFA (-308G>A) and IL-10 (-819C>T) promoter polymorphisms with risk of cervical cancer. Int J Gynecol Cancer 2009; 19:1190-4. [PMID: 19823053 DOI: 10.1111/igc.0b013e3181a3a3af] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Etiology of cervical cancer is associated with excessive inflammation mediated tumorigenesis. Pro and anti-inflammatory cytokines (tumor necrosis factor alpha, TNFA and interleukin, IL-10) are involved in fighting against the tumorigenesis. Therefore, the present study was designed to evaluate the association of TNFA (-308G>A) and IL-10 (-819C>T) gene polymorphism with risk of cervical cancer. One hundred fifty histopathologically confirmed patients with cervical cancer and 162 age, ethnically-matched cervical cytology negative healthy controls were genotyped for TNFA (-308 G>A) and IL-10 (-819 C>T) polymorphisms using PCR-RFLP. Individuals with combination of TNFA -308GA+AA genotype and A allele were at elevated risk of cervical cancer (odds ratio (OR) = 2.24; P = 0.018 and OR, 2.05; P = 0.012). Frequency of IL-10 -819CT+TT genotype combination and T allele was slightly higher in cases as compared with controls but difference was not significant (OR = 1.52; P = 0.069 and OR = 1.38; P = 0.051). In association of genotypes with clinical characteristics, presence of TNFA -308GA+AA genotype conferred high risk for the stages (IB) (OR = 2.86, P = 0.039) and stages (III) (OR = 2.52; P = 0.015) of cervical cancer. In contrast, IL-10 -819TT genotype was not associated with higher risk of clinical characteristics of cervical cancer. In conclusion, individuals with TNFA -308*A allele carriers were at significantly higher risk of cervical cancer particularly early (IB) and advanced stages (III). However, IL-10 (-819C>T) polymorphism was not associated with risk of cervical cancer.
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Affiliation(s)
- HariOm Singh
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, CSMMU, Lucknow, India
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23
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The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women. Cancer Causes Control 2009; 21:23-30. [DOI: 10.1007/s10552-009-9430-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Accepted: 09/08/2009] [Indexed: 10/20/2022]
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Szalmás A, Kónya J. Epigenetic alterations in cervical carcinogenesis. Semin Cancer Biol 2009; 19:144-52. [PMID: 19429477 DOI: 10.1016/j.semcancer.2009.02.011] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2009] [Accepted: 02/13/2009] [Indexed: 01/22/2023]
Abstract
During cervical carcinogenesis, the major etiologic factor, the persistent oncogenic HPV infection itself is not sufficient to immortalize and transform the epithelial host cells. Together with further genetic and epigenetic alterations disrupting the cell cycle control, the host cell acquires immortal phenotype and progresses further to an overt malignant and invasive phenotype. Here, we discuss how cancer-associated epigenetic alterations can affect the expression of papillomaviral as well as host genes in relation to stages representing the multistep process of carcinogenesis. Biomarker roles in clinical diagnosis and prognosis might be assigned to the epigenetic pattern of the involved genes.
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Affiliation(s)
- Anita Szalmás
- Department of Medical Microbiology, Medical and Health Science Center, University of Debrecen, Nagyerdei krt. 98, Debrecen, Hungary
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25
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Impact of methylenetetrahydrofolate reductase (MTHFR) codon (677) and methionine synthase (MS) codon (2756) on risk of cervical carcinogenesis in North Indian population. Arch Gynecol Obstet 2008; 278:517-24. [PMID: 18351371 DOI: 10.1007/s00404-008-0623-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2007] [Accepted: 03/03/2008] [Indexed: 10/22/2022]
Abstract
Cervical cancer continues to be the most common cause of death among women in developing countries. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are critical enzymes of folate metabolic pathways. In this work, we have conducted a case-control study to assess the role of these two polymorphisms in cervical cancer development. We obtained blood samples from 200 women with cervical cancer and from equal matched controls and analysed using PCR-RFLP method. We found that the methylenetetrahydrofolate reductase variant CT and CT+TT genotypes decreased cervix cancer risk, statistically significant (OR:0.30, 95% CI: 0.18-0.51, P<0.001 for CT and OR:0.29, 95% CI: 0.18-0.49, P=0.0000006 for CT+TT). Similarly in those patients who used oral contraceptive with variant CT genotype, there was statistically highly significant reduced risk of cervix cancer (OR:0.25, 95% CI: -0.12-0.49, P<0.001) of methylenetetrahydrofolate reductase gene. For the methionine synthase, 2756 variant AG and AG+GG genotypes were similarly associated with highly significant reduced risk of cervix cancer (OR: 0.13, 95% CI: 0.07-0.26, P<0.001 for AG, and OR: 0.15, 95% CI: 0.08-0.27, P<0.001 for AG+GG) genotypes. In conclusion, our study suggested that methylenetetrahydrofolate reductase and methionine synthase polymorphisms might have protective effect on the risk of cervical cancer in the North Indian women.
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Madkan VK, Cook-Norris RH, Steadman MC, Arora A, Mendoza N, Tyring SK. The oncogenic potential of human papillomaviruses: a review on the role of host genetics and environmental cofactors. Br J Dermatol 2007; 157:228-41. [PMID: 17553059 DOI: 10.1111/j.1365-2133.2007.07961.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Human papillomaviruses (HPVs), with over 100 genotypes, are a very complex group of human pathogenic viruses. In most cases, HPV infection results in benign epithelial proliferations (verrucae). However, oncogenic types of HPV may induce malignant transformation in the presence of cofactors. For example, over 99% of all cervical cancers and a majority of vulval, vaginal, anal and penile cancers are the result of oncogenic HPV types. Such HPV types have been increasingly linked to other epithelial cancers involving the skin, larynx and oesophagus. Although viral infection is necessary for neoplastic transformation, evidence suggests that host and environmental cofactors are also required. Research investigating HPV oncogenesis is complex and quite extensive. The inability to produce mature HPV virions in animal models has been a major limitation in fully elucidating the oncogenic potential and role of associated cofactors in promoting malignant transformation in HPV-infected cells. We have reviewed the literature and provide a brief account of the current understanding of HPV oncogenesis, emphasizing the role of genetic susceptibility, immune response, and environmental and infectious cofactors.
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Affiliation(s)
- V K Madkan
- Center for Clinical Studies, Studies & Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA.
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Mu LN, Cao W, Zhang ZF, Cai L, Jiang QW, You NC, Goldstein BY, Wei GR, Chen CW, Lu QY, Zhou XF, Ding BG, Chang J, Yu SZ. Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary hepatocellular carcinoma (HCC) in a Chinese population. Cancer Causes Control 2007; 18:665-75. [PMID: 17503006 PMCID: PMC4165489 DOI: 10.1007/s10552-007-9012-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2006] [Accepted: 03/30/2007] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Methylenetetrahydrofolate reductase (MTHFR), which is expressed in the liver, may be involved in both DNA methylation and DNA synthesis. It is also indicated as a potential risk factor of liver cancer in patients with chronic liver disease. To date, no study has been conducted on MTHFR and hepatocellular carcinoma (HCC) using a population-based design. The objective of this study was to evaluate the effects of polymorphisms of the MTHFR gene on the risk of primary liver cancer and their possible effect modifications on various environmental risk factors. METHODS A population-based case-control study was conducted in Taixing, China. MTHFR C677T and A1298C were assayed by PCR-RFLP techniques. RESULTS The frequency of MTHFR 677 C/C wild homozygotes genotype was 25.8% in cases, which was lower than that in controls (34.5%). The adjusted odds ratios (ORs) for the MTHFR 677 C/T and T/T genotype were 1.66(95% CI: 1.06-2.61), 1.21(95% CI: 0.65-2.28) respectively when compared with the MTHFR 677 C/C genotype. Subjects carrying any T genotype have the increased risk of 1.55(95% CI: 1.01-2.40) for development of primary hepatocellular carcinoma. A high degree of linkage disequilibrium was observed between the C677T and A1298C polymorphisms, with the D' of 0.887 and p < 0.01. The MTHFR 677 any T genotype was suggested to have potentially more than multiplicative interactions with raw water drinking with p-value for adjusted interaction of 0.03. CONCLUSION We observed that the MTHFR 677 C/T genotype was associated with an increased risk of primary liver cancer in a Chinese population. The polymorphism of MTHFR 677 might modify the effects of raw water drinking on the risk of primary hepatocellular carcinoma.
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Affiliation(s)
- Li-Na Mu
- Department of Epidemiology, Fudan University School of Public Health, Shanghai, China.
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Weng YR, Sun DF, Fang JY, Gu WQ, Zhu HY. Folate levels in mucosal tissue but not methylenetetrahydrofolate reductase polymorphisms are associated with gastric carcinogenesis. World J Gastroenterol 2006; 12:7591-7. [PMID: 17171786 PMCID: PMC4088039 DOI: 10.3748/wjg.v12.i47.7591] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation.
METHODS: Real-time PCR was used to study the expression of tumor related genes in 76 mucosal tissue samples from 38 patients with gastric cancer. Samples from the gastroscopic biopsy tissues of 34 patients with chronic superficial gastritis (CSG) were used as controls. Folate concentrations in these tissues were detected by the FOL ACS: 180 automated chemiluminescence system. MTHFR polymorphisms were analyzed by PCR-RFLP, and the promoter methylation of tumor-related genes was determined by methylation-specific PCR (MSP).
RESULTS: Folate concentrations were significantly higher in CSG than in cancerous tissues. Decreased expression and methylation of c-myc accompanied higher folate concentrations. Promoter hypermethylation and loss of p16INK4A in samples with MTHFR 677CC were more frequent than in samples with the 677TT or 677CT genotype. And the promoter hypermethylation and loss of p21WAF1 in samples with MTHFR 677CT were more frequent than when 677CC or 677TT was present. The 677CT genotype showed a non-significant higher risk for gastric cancer as compared with the 677CC genotype.
CONCLUSION: Lower folate levels in gastric mucosal tissue may confer a higher risk of gastric carcinogenesis through hypomethylation and overexpression of c-myc.
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Affiliation(s)
- Yu-Rong Weng
- Shanghai Institute of Digestive Disease, Shanghai Jiao-Tong University School of Medicine, Renji Hospital, Shanghai 200001, China
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Rao GG, Kurien A, Gossett D, Griffith WF, Coleman RL, Muller CY. A case–control study of methylenetetrahydrofolate reductase polymorphisms in cervical carcinogenesis. Gynecol Oncol 2006; 101:250-4. [PMID: 16297972 DOI: 10.1016/j.ygyno.2005.10.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2005] [Revised: 10/07/2005] [Accepted: 10/14/2005] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are thought to be associated with a varying risk of cervical dysplasia. The purpose of this trial was to study the role of the two common functional MHTFR polymorphisms in a large multiracial population at risk for cervical dysplasia and cancer. METHODS This is a nested case-control study of 376 subjects obtained from cohorts enrolled in an ongoing prospective cervical carcinogenesis protocol. Cases included invasive cancers (n = 51), and high (n = 50) and low (n = 50) grade dysplasia. There were 225 normal controls. Functional MTHFR 677C-->T and 1298A-->C genotypes were identified. Follow-up cytology data were reviewed for the control subjects from the time of study entry until August 2004. RESULTS There is a significant racial difference in allele frequency of the 677C-->T polymorphism (P < 0.005). African-American women had an extremely low prevalence of the 677T allele (8%). There was no significant difference in the frequency of the 677T allele between cases and controls. There is no racial difference in allele frequency of the 1298A-->C polymorphism. Also, no significant difference was found between cases and controls. Of the 51 cancers, no case was homozygous for both aberrant polymorphisms (677T, 1298C), and only 3 cases were heterozygous for both. Follow-up data were available for 129 of 225 control subjects (57%). Only 15 (12%) have had a subsequent abnormal pap, and there was no association with the 677C-->T polymorphism. CONCLUSIONS We confirm a significant difference in the 677T allele frequencies among racial groups. However, there is no association of either the 677C-->T or 1298A-->C polymorphisms in cervical carcinogenesis. There is no role of the combined polymorphism effect in cervical cancer or evidence of prediction for future Pap abnormalities.
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Affiliation(s)
- Gautam G Rao
- Division of Gynecologic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75201, USA
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Powers HJ. Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer. J Nutr 2005; 135:2960S-2966S. [PMID: 16317155 DOI: 10.1093/jn/135.12.2960s] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Epidemiological studies have linked low folate intake with an increased risk of epithelial cancers, including colorectal cancer and cervical cancer. Riboflavin has received much less attention, but there is increasing interest in the well-established role that flavins play in folate metabolism and the possible synergy of a protective effect between these 2 vitamins. Folate plays a key role in DNA synthesis, repair, and methylation, and this forms the basis of mechanistic explanations for a putative role for folate in cancer prevention. The role of folate in these processes may be modulated by genotype for the common C677T thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), homozygosity for which is associated with lower enzyme activity, lower plasma and red blood cell folate, and elevated plasma homocysteine. Riboflavin, as FAD, is a cofactor for MTHFR and there is evidently some interaction among riboflavin status, folate status, and genotype in determining plasma homocysteine, a functional marker of folate status. The MTHFR C677T polymorphism appears to interact with folate and riboflavin in modulating cancer risk in a manner that varies according to cancer site. Most evidence points to a protective effect of this polymorphism for risk of colorectal cancer, but the effect on cervical cancer risk is not clear. The effect of this polymorphism on cancer risk seems to be further modulated by other factors, including alcohol and, in the case of cervical cancer, infection with the human papilloma virus. An additional factor determining the effect of diet and genotype interactions on cancer risk may be the stage of cancer development.
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