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Ye M, Xu G, Zhang L, Kong Z, Qiu Z. Meta Analysis of Methylenetetrahydrofolate Reductase (MTHFR) C677T polymorphism and its association with folate and colorectal cancer. BMC Cancer 2025; 25:169. [PMID: 39875876 PMCID: PMC11776141 DOI: 10.1186/s12885-025-13546-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/16/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND DNA hypomethylation and uracil misincorporation into DNA, both of which have a very important correlation with colorectal carcinogenesis. Folate plays a crucial role in DNA synthesis, acting as a coenzyme in one-carbon metabolism, which involves the synthesis of purines, pyrimidines, and methyl groups. MTHFR, a key enzyme in folate metabolism, has been widely studied in relation to neural tube defects and hypertension, but its role in colorectal cancer remains underexplored. Therefore, understanding the role of folate and MTHFR genes in colorectal cancer may be helpful for potential preventive or therapeutic interventions. In this meta-analysis, the effects of MTHFR genotype and folate intake on colorectal cancer incidence were analyzed. METHODS We searched PubMed,Embase, Web of Science, and CNKI database to identify relevant studies up to January 2024. We included a series of studies on the association of MTHFR C677T genotype and folate intake with colorectal cancer incidence. The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). It included 100 studies (39702 cases and 55718 controls),that investigated the association between the MTHFR C677T polymorphism and colorectal cancer (CRC). Additionally, the analysis incorporated further stratification by ethnic population and geographical region. Furthermore, Six of the studies which clarified high amount of folate might be a protective factor for CRC in all three MTHFR C677T genotype, especially in TT genotype. RESULTS MTHFR 677TT genotype was negatively associated with CRC incidence compared with CC genotype (OR = 0.89; 95% CI: 0.85-0.93; P < 0.00001; Z = 5.17). MTHFR 677CT genotype was not significantly associated with colorectal cancer incidence (OR = 1.00; 95% CI: 0.98,1.03). A negative correlation between TT genotype and CRC was observed in ethnics of Asians (OR = 0.83, 95% CI: 0.76, 0.91), Caucasians (OR = 0.93, 95% CI: 0.88, 0.99) and the region of USA (OR = 0.77, 95% CI: 0.71, 0.85), Asia (OR = 0.93, 95% CI: 0.86, 1.00) and Europe (OR = 0.93, 95% CI:0.87, 1.00),but not in Indian (TT: OR = 1.67, 95% CI: 1.06, 2.63; CT: OR = 1.31, 95% CI: 1.00, 1.73)). Amount folate intakes might reduce the morbidity of CRC for people in MTHFR 677TT genotype (OR = 0.68; 95% CI: 0.48,0.96; P = 0.03). CONCLUSION The analysis showed that the incidence of colorectal cancer was reduced among individuals with TT genotype. The individuals with TT genotype and amount folate intake may collectively improve the incidence of colorectal cancer. While the MTHFR 677TT genotype is associated with a reduced risk of CRC, especially in certain populations, these findings should be interpreted with caution due to the limitations of retrospective studies.
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Affiliation(s)
- Meng Ye
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524023, P.R. China
| | - Guojie Xu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China
| | - Liming Zhang
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524023, P.R. China
| | - Zhihui Kong
- Department of Laboratory Medicine, Jingshan People's Hospital, Jingshan, 431800, P.R. China.
| | - Zhenhua Qiu
- Department of Laboratory Medicine, Affiliated Gaozhou People's Hospital, Guangdong Medical University, Maoming, 525200, P.R. China.
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He Q, Wei Y, Zhu H, Liang Q, Chen P, Li S, Song Y, Liu L, Wang B, Xu X, Dong Y. The combined effect of MTHFR C677T and A1298C polymorphisms on the risk of digestive system cancer among a hypertensive population. Discov Oncol 2024; 15:97. [PMID: 38565713 PMCID: PMC10987447 DOI: 10.1007/s12672-024-00960-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 03/29/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND AND PURPOSE The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in directing folate species towards nucleotide synthesis or DNA methylation. The MTHFR polymorphisms C677T and A1298C have been linked to cancer susceptibility, but the evidence supporting this association has been equivocal. To investigate the individual and joint associations between MTHFR C677T, A1298C, and digestive system cancer in a Chinese hypertensive population, we conducted a population-based case-control study involving 751 digestive system cancer cases and one-to-one matched controls from the China H-type Hypertension Registry Study (CHHRS). METHODS We utilized the conditional logistic regression model to evaluate multivariate odds ratios (ORs) and 95% confidence intervals (CIs) of digestive system cancer. RESULTS The analysis revealed a significantly lower risk of digestive system cancer in individuals with the CT genotype (adjusted OR: 0.71; 95% CI 0.52, 0.97; P = 0.034) and TT genotype (adjusted OR: 0.57; 95% CI 0.40, 0.82; P = 0.003; P for trend = 0.003) compared to those with the 677CC genotype. Although A1298C did not show a measurable association with digestive system cancer risk, further stratification of 677CT genotype carriers by A1298C homozygotes (AA) and heterozygotes (AC) revealed a distinct trend within these subgroups. CONCLUSION These findings indicate a potential protective effect against digestive system cancer associated with the T allele of MTHFR C677T. Moreover, we observed that the presence of different combinations of MTHFR polymorphisms may contribute to varying susceptibilities to digestive system cancer.
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Affiliation(s)
- Qiangqiang He
- Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, No. 2279, Lishui Road. Nanshan District, Shenzhen, 518055, Guangdong, China
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
| | - Yaping Wei
- College of Public Health, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Hehao Zhu
- School of Science, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China
| | - Qiongyue Liang
- State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China
| | - Ping Chen
- College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China
- Inspection and Testing Center, Key Laboratory of Cancer FSMP for State Market Regulation, Shenzhen, 518057, China
| | - Shuqun Li
- Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, 100038, China
| | - Yun Song
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
| | - Lishun Liu
- Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, No. 2279, Lishui Road. Nanshan District, Shenzhen, 518055, Guangdong, China
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
- Guangdong Key Laboratory of H-Type Hypertension and Stroke Precision Prevention Research and Development Enterprise, Shenzhen, 518057, China
| | - Binyan Wang
- Shenzhen Evergreen Medical Institute, Shenzhen, 518057, Guangdong, China
- Institute of Biomedicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xiping Xu
- National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health, Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yuhan Dong
- Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, No. 2279, Lishui Road. Nanshan District, Shenzhen, 518055, Guangdong, China.
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Zhang W, Chen L, Cao G, Wang F, Chen E. Relationship between MTHFR gene polymorphism and risk of thrombosis in postoperative patients with colorectal cancer. Exp Ther Med 2023; 26:588. [PMID: 38023362 PMCID: PMC10665995 DOI: 10.3892/etm.2023.12287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 04/26/2023] [Indexed: 12/01/2023] Open
Abstract
An association between the methylenetetrahydrofolate reductase (MTHFR) C667T genotype and the risk of colorectal cancer, as well as a link between MTHFR gene polymorphism and thrombosis, have been revealed. However, the connection between MTHFR gene polymorphism and the risk of thrombosis in patients with colorectal cancer has remained to be fully elucidated. The present study investigated the link between MTHFR gene polymorphism and basic clinical data, postoperative D-dimer (DDi), postoperative thromboelastogram and postoperative thrombosis in 591 patients who underwent surgery for colorectal cancer. Postoperative DDi, thromboelastogram and postoperative thrombosis were not significantly different among patients with colorectal cancer and different MTHFR genotypes. While the results were 'negative', the present study may help physicians understand that it is not necessary to detect MTHFR polymorphism for therapeutic purposes. Regarding the danger of venous thrombosis, more focus should be placed on the standardized procedural enforcement system for deep vein thrombosis prevention for patients undergoing pelvic and abdominal surgery.
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Affiliation(s)
- Wei Zhang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Li Chen
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Gaoyang Cao
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Fei Wang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Engeng Chen
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
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Mohd Y, Kumar P, Kuchi Bhotla H, Meyyazhagan A, Balasubramanian B, Ramesh Kumar MK, Pappusamy M, Alagamuthu KK, Orlacchio A, Keshavarao S, Sampathkumar P, Arumugam VA. Transmission Jeopardy of Adenomatosis Polyposis Coli and Methylenetetrahydrofolate Reductase in Colorectal Cancer. J Renin Angiotensin Aldosterone Syst 2021; 2021:7010706. [PMID: 34956401 PMCID: PMC8683247 DOI: 10.1155/2021/7010706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/14/2021] [Accepted: 11/18/2021] [Indexed: 11/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the globally prevalent and virulent types of cancer with a distinct alteration in chromosomes. Often, any alterations in the adenomatosis polyposis coli (APC), a tumor suppressor gene, and methylenetetrahydrofolate reductase (MTHFR) gene are related to surmise colorectal cancer significantly. In this study, we have investigated chromosomal and gene variants to discern a new-fangled gene and its expression in the southern populations of India by primarily spotting the screened APC and MTHFR variants in CRC patients. An equal number of CRC patients and healthy control subjects (n = 65) were evaluated to observe a chromosomal alteration in the concerted and singular manner for APC and MTHFR genotypes using standard protocols. The increasing prognosis was observed in persons with higher alcoholism and smoking (P < 0.05) with frequent alterations in chromosomes 1, 5, 12, 13, 15, 17, 18, 21, and 22. The APC Asp 1822Val and MTHFR C677T genotypes provided significant results, while the variant alleles of this polymorphism were linked with an elevated risk of CRC. Chromosomal alterations can be the major cause in inducing carcinogenic outcomes in CRCs and can drive to extreme pathological states.
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Affiliation(s)
- Younis Mohd
- Medical Genetics and Epigenetics Laboratory, Department of Human Genetics and Molecular Biology, School of Life Sciences, Bharathiar University, 641046 Tamil Nadu, India
| | - Parvinder Kumar
- Department of Zoology, Jammu University, Jammu, 180006 Jammu and Kashmir, India
- Institution of Human Genetics, Jammu University, Jammu, 180006 Jammu and Kashmir, India
| | - Haripriya Kuchi Bhotla
- Human Genetics Laboratory, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, 461046 Tamil Nadu, India
| | - Arun Meyyazhagan
- Department of Life Sciences, CHRIST (Deemed to be University), Bangalore 560029, India
| | | | - Mithun Kumar Ramesh Kumar
- Department of General Surgery, Mahatma Gandhi Medical College and Research Institute, Pillaiyarkuppam, 607403 Pondicherry, India
| | - Manikantan Pappusamy
- Department of Life Sciences, CHRIST (Deemed to be University), Bangalore 560029, India
| | - Karthick Kumar Alagamuthu
- Department of Biotechnology, Selvamm Arts and Science College (Autonomous), Namakkal, Tamil Nadu 637003, India
| | - Antonio Orlacchio
- Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Sasikala Keshavarao
- Human Genetics Laboratory, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, 461046 Tamil Nadu, India
| | - Palanisamy Sampathkumar
- Department of Chemistry and Biosciences, SASTRA Deemed to be University, Kumbakonam Tamil Nadu 612001, India
| | - Vijaya Anand Arumugam
- Medical Genetics and Epigenetics Laboratory, Department of Human Genetics and Molecular Biology, School of Life Sciences, Bharathiar University, 641046 Tamil Nadu, India
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Ramos-Esquivel A, Chinchilla-Monge R, Abbas J, Valle M. C677T and A1298C MTHFR gene polymorphisms and response to fluoropyrimidine-based chemotherapy in Mestizo patients with metastatic colorectal cancer. Pharmacogenet Genomics 2021; 31:191-199. [PMID: 34116533 DOI: 10.1097/fpc.0000000000000440] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To assess the association between C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and response to first-line fluoropyrimidine-based chemotherapy for metastatic colorectal adenocarcinoma. METHODS A total of 68 patients were prospectively followed up in San Juan de Dios Hospital (San José, Costa Rica) from January 2019 to November 2020. Patients received first-line therapy with capecitabine or 5-fluorouracil in combination with oxaliplatin or irinotecan. Germline and somatic DNA was extracted from blood samples and paraffin-embedded tissue, respectively. Overall response rate (partial response + complete response) was assessed according to RECIST 1.1 criteria. Cox regression models were performed to identify the effect of MTHFR C677T and A1298C SNPs on progression-free survival (PFS) and overall survival (OS) (NCT registration number: 03852290). RESULTS Patients harboring one or both T alleles of the MTHFR C677T SNP had better overall response than homozygous wild-type individuals [odds ratio (OR): 3.21; 95% confidence interval (CI), 1.05-9.81; P = 0.03]. No association was found between the MTHFR A1298C genotypes and overall response (OR: 0.75; 95% CI, 0.26-2.20; P = 0.60). Patients with the MTHFR 677 TT and CT genotypes had longer PFS than CC individuals (hazard ratio: 0.53; 95% CI, 0.28-0.98; P = 0.045), even after adjustment for confounders (hazard ratio: 0.50; 95% CI, 0.25-0.98; P = 0.04). We found no association between the MTHFR A1298C SNP and PFS (hazard ratio: 1.35; 95% CI, 0.72-2.55; P = 0.34). None of the SNPs was associated with OS. CONCLUSION Patients carrying at least one mutant allele of the MTHFR C677T SNP had a better overall response and longer PFS than wild-type homozygous patients.
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Affiliation(s)
- Allan Ramos-Esquivel
- Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigaciones en Hematología y Trastornos Afines, CIHATA, Universidad de Costa Rica
| | | | - Jad Abbas
- Departamento de Patología, Hospital Calderón Guardia, Caja Costarricense de Seguro Social, San José, San Pedro, Costa Rica
| | - Marta Valle
- Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
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Yari A, Meybodi SME, Karam ZM, Samoudi A, Hashemi F, Aalipour M, Abadi MFS, Dabiri S. Association of MTHFR 677C>T and 1298A>C genetic polymorphisms with colorectal cancer: Genotype and haplotype analysis in a Southeast Iranian population. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Vasavi M, Ponnala S, Gujjari K, Boddu P, Bharatula RS, Prasad R, Ahuja YR, Hasan Q. Dna Methylation in Esophageal Diseases Including Cancer: Special Reference to hMLH1 Gene Promoter Status. TUMORI JOURNAL 2019; 92:155-62. [PMID: 16724696 DOI: 10.1177/030089160609200212] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and Background Chronic inflammation leading to malignancy in the esophagus may be due to errors in mismatch repair (MMR) genes such as hMLH1. Promoter hypermethylation has been suggested as the main cause of hMLH1 silencing. In this study we assessed hMLH1 promoter hypermethylation in a range of esophageal diseases. Further, we evaluated the role of factors affecting the methylation cycle: (1) methyt-enetetrahydrofolate reductase (MTHFR) C677T mutation and (2) serum homocysteine levels. Methods We endoscopically and histologically categorized 124 paired tissue and blood samples from patients into cancer, precancer, reflux esophagitis, other inflammatory esophagitis and controls (endoscopically normal). Restriction enzyme-based methylation analysis was carried out to assess hMLH1 promoter hypermethylation. Results and Conclusions hMLH1 promoter hypermethylation in tissue was seen in 63.5% of patients with cancer and 53.8% of those with precancer, which was significantly increased when compared with controls (P <0.001). There appears to be an increasing degree of hMLH1 hypermethylation with disease progression. Patients with gastroesophageal reflux disease (GERD) showed a high degree of hMLH1 hypermethylation (88.8%), indicating that local environment due to reflux may be promoting hypermethylation. We suggest that GERD is a progressive condition with an increased risk for developing into cancer. Only 14.5% of cases exhibited hypermethylation both in tissue and blood. Hence, we conclude that hMLH1 promoter hypermethylation is a tissue-specific change in the esophagus and blood testing cannot be used as a noninvasive tool to assess it. DNA methylation is dependent on the methylation cycle; MTHFR is a major enzyme in this pathway. MTHFR mutations did not correlate with hypermethylation or clinical pathology (P >0.5). Elevated homocysteine levels, independent of MTHFR mutation, correlated significantly with hMLH1 hypermethylation in tissue (P <0.005). Our study shows that hMLH1 hypermethylation in tissue may be the primary event caused by endogenous/exogenous factors in esophageal diseases, aiding disease progression.
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Affiliation(s)
- Mohan Vasavi
- Department of Genetics and Molecular Medicine, Gastroenterology and Biochemistry, Kamineni Hospitals, Hyderabad, India
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Shiao SPK, Grayson J, Yu CH. Gene-Metabolite Interaction in the One Carbon Metabolism Pathway: Predictors of Colorectal Cancer in Multi-Ethnic Families. J Pers Med 2018; 8:E26. [PMID: 30082654 PMCID: PMC6164460 DOI: 10.3390/jpm8030026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 07/14/2018] [Accepted: 08/01/2018] [Indexed: 02/07/2023] Open
Abstract
For personalized healthcare, the purpose of this study was to examine the key genes and metabolites in the one-carbon metabolism (OCM) pathway and their interactions as predictors of colorectal cancer (CRC) in multi-ethnic families. In this proof-of-concept study, we included a total of 30 participants, 15 CRC cases and 15 matched family/friends representing major ethnic groups in southern California. Analytics based on supervised machine learning were applied, with the target variable being specified as cancer, including the ensemble method and generalized regression (GR) prediction. Elastic Net with Akaike's Information Criterion with correction (AICc) and Leave-One-Out cross validation GR methods were used to validate the results for enhanced optimality, prediction, and reproducibility. The results revealed that despite some family members sharing genetic heritage, the CRC group had greater combined gene polymorphism-mutations than the family controls (p < 0.1) for five genes including MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, and DHFR 19bp. Blood metabolites including homocysteine (7 µmol/L), methyl-folate (40 nmol/L) with total gene mutations (≥4); age (51 years) and vegetable intake (2 cups), and interactions of gene mutations and methylmalonic acid (MMA) (400 nmol/L) were significant predictors (all p < 0.0001) using the AICc. The results were validated by a 3% misclassification rate, AICc of 26, and >99% area under the receiver operating characteristic curve. These results point to the important roles of blood metabolites as potential markers in the prevention of CRC. Future intervention studies can be designed to target the ways to mitigate the enzyme-metabolite deficiencies in the OCM pathway to prevent cancer.
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Affiliation(s)
- S Pamela K Shiao
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - James Grayson
- Hull College of Business, Augusta University, Augusta, GA 30912, USA.
| | - Chong Ho Yu
- Department of Psychology, Azusa Pacific University, Azusa, CA 91702, USA.
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Shiao SPK, Lie A, Yu CH. Meta-analysis of homocysteine-related factors on the risk of colorectal cancer. Oncotarget 2018; 9:25681-25697. [PMID: 29876016 PMCID: PMC5986656 DOI: 10.18632/oncotarget.25355] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 04/24/2018] [Indexed: 02/07/2023] Open
Abstract
The major objective of this meta-analysis was to examine the association between homocysteine and related measurements with the risk of colorectal cancer (CRC) and adenomatous polyps (AP). Many studies presented an association between methyltetrahydrofolate reductase (MTHFR) gene polymorphisms and risk of CRC. Yet, there have been variances on what homocysteine-related and dietary factors play on the risk of CRC or AP, in association with folate-related one carbon metabolism pathways. We pooled analyses to examine comprehensively all homocysteine related factors including blood tests measurements, dietary, and lifestyle factors for their associations with the risk of CRC and AP. We located 86 articles published from 1995 to 2017. The results revealed that elevated homocysteine levels and decreased vitamin B12 levels in the blood were associated with increased risks of CRC and AP, with case-control studies having greater significant effect sizes compared to that of cohort-control studies. Decreased methionine and vitamin B6 levels in the blood increased the risk of CRC. MTHFR 677 TT and CT polymorphisms were interacting with elevated homocysteine levels to increase the risk of CRC. Decreased dietary fiber, methionine, vitamin B9 or folate, and vitamin B6 intakes were associated with increased risks of CRC; whereas, increased dietary B12 intake, alcohol intake, and smoking were associated with increased risk of CRC. Further studies can be conducted to examine the mechanistic differences of blood levels of homocysteine-related and dietary factors, including different types of dietary fiber, for their effects on decreasing the homocysteine toxicity to prevent CRC.
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Affiliation(s)
- S Pamela K Shiao
- College of Nursing and Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Amanda Lie
- Citrus Valley Health Partners, Foothill Presbyterian Hospital, Glendora, CA, USA
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Xu L, Qin Z, Wang F, Si S, Li L, Lin P, Han X, Cai X, Yang H, Gu Y. Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis. Biosci Rep 2017; 37:BSR20170917. [PMID: 29089462 PMCID: PMC5719002 DOI: 10.1042/bsr20170917] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 10/13/2017] [Accepted: 10/31/2017] [Indexed: 12/19/2022] Open
Abstract
The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer (CRC) susceptibility has been researched in numerous studies. However, the results of these studies were controversial. Therefore, the objective of this meta-analysis was to offer a more convincible conclusion about such association with more included studies. Eligible studies published till May 1, 2017 were searched from PubMed, Embase, Web of Science, and CNKI database about such association. Pooled odds ratios (ORs) together with 95% confidence intervals (CIs) were calculated to evaluate such association. And the Begg's funnel plot and Egger's test were applied to assess the publication bias. This meta-analysis contained 37049 cases and 52444 controls from 87 publications with 91 eligible case-control studies. Because of lack of data for a particular genotype in several studies, all the included studies were analysed barely in the dominant model. Originally, there was no association between MTHFR C677T polymorphism and CRC susceptibility (OR =0.99, 95% CI =0.94-1.05). After excluding 13 studies according to their heterogeneity and publication bias, rs1801133 polymorphism was found to reduce the risks of CRC significantly (OR =0.96, 95% CI =0.94-0.99). In the subgroup analysis of ethnicity, there was a significant association in Asians (OR =0.94, 95% CI =0.89-1.00). Furthermore, when stratified by the source of controls and genotyping methods, the positive results were observed in population-based control group (OR =0.97, 95% CI =0.93-1.00) and PCR-restriction fragment length polymorphism (PCR-RFLP) method (OR =0.95, 95% CI =0.91-0.99. The results of the meta-analysis suggested that MTHFR C677T polymorphism was associated with CRC susceptibility, especially in Asian population.
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Affiliation(s)
- Lingyan Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhiqiang Qin
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Feng Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Shuhui Si
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Lele Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Peinan Lin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiao Han
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiaomin Cai
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Haiwei Yang
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yanhong Gu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Methylenetetrahydrofolate reductase gene polymorphism in endometrial cancer: A systematic review and meta-analysis. Taiwan J Obstet Gynecol 2016; 54:546-50. [PMID: 26522108 DOI: 10.1016/j.tjog.2015.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 02/24/2015] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE We conducted a meta-analysis of case-controlled prospective or retrospective studies to assess the effect of MTHFR polymorphisms on the risk of developing endometrial cancer. MATERIALS AND METHODS PubMed, Cochrane, EMBASE, and ISI Web of Knowledge were searched (up to March 2014) for prospective or retrospective case-controlled studies that investigated the association of three MTHFR polymorphisms (rs180113 [C677T], rs1801131 [A1289C], and rs2274976 [G1793A]) with endometrial cancer. RESULTS The patient population included subjects from three separate countries: China, Spain, and the USA. Only one study reported quantitative findings for MTHFR G1793A and, consequently, this polymorphism was not evaluated in our analysis. There were no significant associations of any MTHFR C677T or MTHFR A1298C alleles or genotypes with endometrial cancer (all p > 0.300). CONCLUSION This meta-analysis does not support the association of endometrial cancer with two common MTHFR polymorphisms from this patient population.
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12
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Rai V. Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations. Asian Pac J Cancer Prev 2016; 16:8093-100. [DOI: 10.7314/apjcp.2015.16.18.8093] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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13
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Farias N, Ho N, Butler S, Delaney L, Morrison J, Shahrzad S, Coomber BL. The effects of folic acid on global DNA methylation and colonosphere formation in colon cancer cell lines. J Nutr Biochem 2015; 26:818-26. [PMID: 25804133 DOI: 10.1016/j.jnutbio.2015.02.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 02/18/2015] [Accepted: 02/20/2015] [Indexed: 02/07/2023]
Abstract
Folate and its synthetic form, folic acid (FA), are essential vitamins for the regeneration of S-adenosyl methionine molecules, thereby maintaining adequate cellular methylation. The deregulation of DNA methylation is a contributing factor to carcinogenesis, as alterations in genetic methylation may contribute to stem cell reprogramming and dedifferentiation processes that lead to a cancer stem cell (CSC) phenotype. Here, we investigate the potential effects of FA exposure on DNA methylation and colonosphere formation in cultured human colorectal cancer (CRC) cell lines. We show for the first time that HCT116, LS174T, and SW480 cells grown without adequate FA demonstrate significantly impaired colonosphere forming ability with limited changes in CD133, CD166, and EpCAM surface expression. These differences were accompanied by concomitant changes to DNA methyltransferase (DNMT) enzyme expression and DNA methylation levels, which varied depending on cell line. Taken together, these results demonstrate an interaction between FA metabolism and CSC phenotype in vitro and help elucidate a connection between supplemental FA intake and CRC development.
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Affiliation(s)
- Nathan Farias
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Nelson Ho
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Stacey Butler
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Leanne Delaney
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | - Jodi Morrison
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
| | | | - Brenda L Coomber
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
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Keshteli AH, Baracos VE, Madsen KL. Hyperhomocysteinemia as a potential contributor of colorectal cancer development in inflammatory bowel diseases: A review. World J Gastroenterol 2015; 21:1081-1090. [PMID: 25632180 PMCID: PMC4306151 DOI: 10.3748/wjg.v21.i4.1081] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 09/13/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
Homocysteine is an amino acid generated metabolically by the S-adenosylmethionine-dependent transmethylation pathway. In addition to being a well-known independent risk factor for coronary heart disease, is also a risk factor for cancer. Patients suffering from inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn’s disease are at increased risk of developing colorectal cancer in comparison to healthy individuals. Furthermore, the risk of hyperhomocysteinaemia is significantly higher in IBD patients when compared with controls. In the present article, we review the mechanisms in which hyperhomocysteinemia may contribute to increased risk of colorectal cancer in IBD patients.
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Murthy J, Lakkakula S, Gurramkonda VB, Pathapati RM, Maram R, Lakkakula BVKS. CBS c.844ins68 Polymorphism Frequencies in Control Populations: Implications on Nonsyndromic Cleft Lip With or Without Cleft Palate. Cleft Palate Craniofac J 2015; 52:49-53. [PMID: 24437588 DOI: 10.1597/13-051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with substantial clinical and social impact. Folate deficiency is one of the factors that have been associated with increased risk for NSCLP. Polymorphisms in folate and homocysteine pathway genes may act as susceptibility factors. OBJECTIVE The objective of this study was to evaluate prevalence estimates of cystathionine beta-synthase (CBS) insertion of 68-bp (c.844ins68) polymorphisms and their correlation with NSCLP. MATERIAL AND METHODS A total of 236 unrelated individuals from seven Indian populations and an additional 355 cases with NSCLP and 357 controls without NSCLP were included in this study. We investigated the CBS c.844ins68 polymorphism in all samples. Genotyping was performed with polymerase chain reaction and electrophoresis. The data were statistically analyzed using the chi-square test. RESULTS The CBS c.844ins68 allele is present in six of the seven populations analyzed, and allele frequencies range from 1.5% in Balija to 9.1% in Sugali populations. The CBS c.844ins68 polymorphism showed a significant protective effect on NSCLP at both genotype (WW versus WI: odds ratio [OR] = 0.54, 95% confidence interval [CI] = 0.31 to 0.95, P = .149) and allele levels (W versus I: OR = 0.56, 95% CI = 0.32 to 0.96, P = .033). CONCLUSIONS The current study observed significant differences in the frequency of the CBS 844ins68 allele across populations. There is a significant association between CBS c.844ins68 polymorphism and cleft lip and palate in the Indian population. Additional studies are warranted to identify the functional variants in the genes controlling homocysteine as etiological contributors to the formation of oral clefts.
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Is right-sided colon cancer different to left-sided colorectal cancer? - a systematic review. Eur J Surg Oncol 2014; 41:300-8. [PMID: 25468456 DOI: 10.1016/j.ejso.2014.11.001] [Citation(s) in RCA: 312] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 11/03/2014] [Indexed: 11/21/2022] Open
Abstract
Colorectal cancer (CRC) exhibits differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. This review focuses on the latest developments in epidemiological and scientific studies, which have enhanced our understanding on the underlying genetic and immunological differences between the proximal (right-sided) colon and the distal (left-sided) colorectum. The different ways in which environmental risk factors influence the pathogenesis of CRC depending on its location and the variations in surgical and oncological outcomes are also discussed in this review. In the current era of personalized medicine, we aim to reiterate the importance of tumor location in management of CRC and the implication on future clinical and scientific research.
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Gupta S, Bhaskar PK, Bhardwaj R, Chandra A, Chaudhry VN, Chaudhry P, Ali A, Mukherjee A, Mutsuddi M. MTHFR C677T predisposes to POAG but not to PACG in a North Indian population: a case control study. PLoS One 2014; 9:e103063. [PMID: 25054348 PMCID: PMC4108368 DOI: 10.1371/journal.pone.0103063] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 06/25/2014] [Indexed: 01/18/2023] Open
Abstract
Hyperhomocysteinemia induced by the C677T genetic variant in MTHFR (methylenetetrahydrofolate reductase) has been implicated in neuronal cell death of retinal ganglion cells (RGC), which is a characteristic feature of glaucoma. However, association of MTHFR C677T with glaucoma has been controversial because of inconsistent results across association studies. Association between MTHFR C677T and glaucoma has not been reported in Indian population. Therefore, with a focus on neurodegenerative death of RGC in glaucoma, the current study aimed to investigate association of MTHFR C677T with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a North Indian population. A total of 404 participants (231 patients and 173 controls) were included in this study. Genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. A few random samples were also tested by direct sequencing. Genotypic and allelic distributions of the POAG and PACG cohorts were compared to that of controls by chi-square test and odds ratios were reported with 95% confidence intervals. Genotypic and allelic distributions between POAG cases and controls were significantly different (p = 0.03 and p = 0.01 respectively). Unlike POAG, we did not find significant difference in the genotypic and allelic distributions of C677T between PACG cases and controls (p>0.05). We also observed a higher proportion of TT associated POAG in females than that in males. However, this is a preliminary indication of gender specific risk of C677T that needs to be replicated in a larger cohort of males and females. The present investigation on MTHFR C677T and glaucoma reveals that the TT genotype and T allele of this polymorphism are significant risk factors for POAG but not for PACG in North Indian population. Ours is the first report demonstrating association of MTHFR C677T with POAG but not PACG in individuals from North India.
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Affiliation(s)
- Shashank Gupta
- Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, India
| | - Pradeep Kumar Bhaskar
- Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, India
| | - Ritu Bhardwaj
- Department of Zoology, Banaras Hindu University, Varanasi, India
| | - Abhishek Chandra
- Department of Ophthalmology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | | | | | - Akhtar Ali
- Centre for Genetic Disorders, Banaras Hindu University, Varanasi, India
| | - Ashim Mukherjee
- Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, India
| | - Mousumi Mutsuddi
- Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, India
- * E-mail:
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Ghasemi S, Tavakoli A, Moghadam M, Zargar MA, Abbaspour M, Hatamnejadian N, Ebrahimi A. Risk of prostate cancer and thrombosis-related factor polymorphisms. Biomed Rep 2013; 2:53-56. [PMID: 24649068 DOI: 10.3892/br.2013.180] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 09/11/2013] [Indexed: 12/25/2022] Open
Abstract
Venous thromboembolism (VTE) is a complication commonly encountered in cancer patients and is considered to be a major cause of morbidity and mortality. The genetic polymorphisms of thrombophilic factors in cancer patients have been focused on during the last few years. However, the number of available studies on the association between prostate cancer and thromboembolic diseases is limited. Prostate cancer is one of the four major types of cancer and its development is affected by a variety of environmental and genetic factors. In the present study we aimed to focus on the effects of thromboembolic factor gene variations on the risk of prostate cancer. In order to conduct our prospective study, we used amplification-refractory mutation system-polymerase chain reaction to investigate three polymorphisms [factor V Leiden (FVL) G1691A, factor II (prothrombin, PTH) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T] in prostate cancer patients, via comparison with normal individuals. The results demonstrated no significant differences in FVL and PTH gene variations between cases and controls (P>0.05). Although some cases with the T allele of MTHFR 677 were identified, no significant solidarity was established by statistical analysis (P>0.05). Therefore, non-genetic factors that may disturb homeostatic balance should also be considered in future studies, in order to determine the exact association between VTE and prostate cancer.
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Affiliation(s)
| | - Aydin Tavakoli
- Parseh Medical Genetics Counseling Center, Tehran, Islamic Republic of Iran
| | - Mohamad Moghadam
- Hematology Research Center, Shiraz University of Medical Science, Shiraz, Islamic Republic of Iran
| | | | - Maryam Abbaspour
- Parseh Medical Genetics Counseling Center, Tehran, Islamic Republic of Iran
| | | | - Ahmad Ebrahimi
- Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
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Impact of the MTHFR C677T polymorphism on colorectal cancer in a population with low genetic variability. Int J Colorectal Dis 2013; 28:1187-93. [PMID: 23422951 DOI: 10.1007/s00384-013-1644-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2013] [Indexed: 02/08/2023]
Abstract
PURPOSES Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis by its role in DNA methylation, repair, and synthesis. We analyzed the impact of MTHFR C677T polymorphism in colorectal cancer in a region of the Tenerife Island whose population has a history of genetic isolation and a low genetic variability. This allows analyzing the effects of the polymorphism that are not due to interactions with different genetic variants. METHODS Genomic DNA of 50 Spanish sporadic colorectal cancer (CRC) patients and 103 controls was analyzed by PCR/RFLP and sequencing. RESULTS The T allele is more frequent in controls than in patients (P < 0.01). The variant (T) carriers displayed significant odds ratio values for the CT heterozygotes (P = 0.026) and even when grouping heterozygote (CT) and homozygotes (TT) (P = 0.015). Patients carriers of the variant T (CT y TT) show a higher survival rate after chemotherapy than the CC homozygotes (log rank; P = 0.001). CONCLUSIONS The MTHRF C677T variant has a protective effect on CRC development in a population with low allelic variability and an optimal intake of folic acid. Moreover, patients carrying the variant (T) show a better prognosis after 5-fluorouracil/folinic acid-based chemotherapy.
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Yousef AM, Shomaf M, Berger S, Ababneh N, Bobali Y, Ali D, Al-Hasan S, Diab O, Ismail S. Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Colorectal Cancer among Jordanian Population. Asian Pac J Cancer Prev 2013; 14:4559-65. [DOI: 10.7314/apjcp.2013.14.8.4559] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Zhao M, Li X, Xing C, Zhou B. Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with colorectal cancer risk: A meta-analysis. Biomed Rep 2013; 1:781-791. [PMID: 24649029 DOI: 10.3892/br.2013.134] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 07/08/2013] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. This meta-analysis was conducted to determine the effect of methylenetetrahydrofolate reductase (MTHFR) mutants on the risk of CRC. A literature search was conducted on PubMed, Medline and the China National Knowledge Infrastructure (CNKI) databases. Eligible studies were collected based on rigorous criteria of inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the fixed- or random-effects model. After all the studies were pooled, the OR of CRC for individuals carrying the MTHFR 677TT genotype, compared to the CC genotype, was 0.89 (95% CI: 0.82-0.97). When analyzed by ethnicity, Asians with the MTHFR 1298CC genotype exhibited a decreased risk of CRC (OR=0.69; 95% CI: 0.54-0.89). In a mixed population, a significantly reduced risk of CRC was observed among carriers of the 677TT (OR=0.86; 95% CI: 0.76-0.96) and the 1298CC (OR=0.82; 95% CI: 0.69-0.98) genotypes, compared to the wild-type homozygous genotype. In the subgroup of colon cancer, the OR of 677TT vs. CC+CT was 0.83 (95% CI: 0.72-0.96) and the OR of 1298CC vs. AA+AC was 0.81 (95% CI: 0.69-0.96). In the rectal cancer subgroup, the OR of 677TT vs. CC+CT was 0.86 (95% CI: 0.77-0.97). Therefore, this meta-analysis suggested that the MTHFR 677T and 1298C alleles were associated with a low risk of CRC.
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Affiliation(s)
- Mengmeng Zhao
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning 110001, P.R. China ; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, Liaoning 110001, P.R. China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning 110001, P.R. China ; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, Liaoning 110001, P.R. China
| | - Chengzhong Xing
- Department of Anorectal Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning 110001, P.R. China ; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, Liaoning 110001, P.R. China
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Jung M, Lee CH, Park HS, Lee JH, Kang YA, Kim SK, Chang J, Kim DJ, Rha SY, Kim JH, Cho BC. Pharmacogenomic assessment of outcomes of pemetrexed-treated patients with adenocarcinoma of the lung. Yonsei Med J 2013; 54:854-64. [PMID: 23709418 PMCID: PMC3663241 DOI: 10.3349/ymj.2013.54.4.854] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
PURPOSE The main objective of this study was to evaluate the association between polymorphisms of the target genes of pemetrexed and clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with pemetrexed. MATERIALS AND METHODS We assessed polymorphisms at 8 sites in 4 genes [thymidylate synthase (TS), dihydrofolate reductase (DHFR; 1610, 680, 317, intron 1), methylenetetrahydrofolate reductase (MTHFR; 677, 1298), glycinamide ribonucleotide formyl transferase (GARFT; 2255)] associated with pemetrexed metabolism using polymerase chain reaction, gene scanning, and restriction fragment length polymorphism analysis in 90 patients with adenocarcinoma of the lung. RESULTS Survival was significantly longer with pemetrexed in patients with TS 3RGCC/3RGCC or 3RGGC/3RGGC compared with the other groups (PFS; 5.2 months vs. 3.7 months, p=0.03: OS; 31.8 months vs. 18.5 months, p=0.001). Patients with DHFR 680CC experienced fatigue more frequently (50% vs. 8.6%, p=0.008). Polymorphisms of MTHFR and GARFT were not significantly associated with clinical outcomes of pemetrexed. CONCLUSION The TS genotype was associated with survival and one DHFR polymorphism was associated with fatigue in NSCLC patients treated with pemetrexed. Further large prospective studies are required to identify other biomarkers that affect patients being treated with pemetrexed for adenocarcinoma of the lung.
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Affiliation(s)
- Minkyu Jung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Chul Ho Lee
- Department of Clinical Genetics, Yonsei University College of Medicine, Seoul, Korea
| | - Hyung Soon Park
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hyun Lee
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
| | - Young Ae Kang
- Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Se Kyu Kim
- Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Joon Chang
- Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dae Joon Kim
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Sun Young Rha
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Joo Hang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Byoung Chul Cho
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Teng Z, Wang L, Cai S, Yu P, Wang J, Gong J, Liu Y. The 677C>T (rs1801133) polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies. PLoS One 2013; 8:e55332. [PMID: 23437053 PMCID: PMC3577825 DOI: 10.1371/journal.pone.0055332] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 12/20/2012] [Indexed: 12/31/2022] Open
Abstract
Background The 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene is considered to have a significant effect on colorectal cancer susceptibility, but the results are inconsistent. In order to investigate the association between the MTHFR 677C>T polymorphism and the risk of colorectal cancer, a meta-analysis was held based on 71 published studies. Methods Eligible studies were identified through searching the MEDLINE, EMBASE, PubMed, Web of Science, Chinese Biomedical Literature database (CBM) and CNKI database. Odds ratios (OR) and 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with x2-based Q-test. Begg's and Egger's test were also carried out to evaluate publication bias. Sensitive and subgroup analysis were also held in this meta-analysis. Results Overall, 71 publications including 31,572 cases and 44,066 controls were identified. The MTHFR 677 C>T variant genotypes are significantly associated with increased risk of colorectal cancer. In the stratified analysis by ethnicity, significantly increased risks were also found among Caucasians for CC vs TT (OR = 1.076; 95%CI = 1.008–1.150; I2 = 52.3%), CT vs TT (OR = 1.102; 95%CI = 1.032–1.177; I2 = 51.4%) and dominant model (OR = 1.086; 95%CI = 1.021–1.156; I2 = 53.6%). Asians for CC vs TT (OR = 1.226; 95%CI = 1.116–1.346; I2 = 55.3%), CT vs TT (OR = 1.180; 95%CI = 1.079–1.291; I2 = 36.2%), recessive (OR = 1.069; 95%CI = 1.003-1.140; I2 = 30.9%) and dominant model (OR = 1.198; 95%CI = 1.101-1.303; I2 = 52.4%), and Mixed populations for CT vs TT (OR = 1.142; 95%CI = 1.005-1.296; I2 = 0.0%). However, no associations were found in Africans for all genetic models. Conclusion This meta-analysis suggests that the MTHFR 677C>T polymorphism increases the risk for developing colorectal cancer, while there is no association among Africans found in subgroup analysis by ethnicity.
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Affiliation(s)
- Zan Teng
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Lei Wang
- Department of Geriatrics, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Shuang Cai
- Department of Pharmacy, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Ping Yu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Jin Wang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Jing Gong
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Yunpeng Liu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
- * E-mail:
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Figueiredo JC, Levine AJ, Crott JW, Baurley J, Haile RW. Folate-genetics and colorectal neoplasia: what we know and need to know next. Mol Nutr Food Res 2013; 57:607-27. [PMID: 23401104 DOI: 10.1002/mnfr.201200278] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 10/11/2012] [Accepted: 11/07/2012] [Indexed: 12/18/2022]
Abstract
SCOPE The metabolism of folate involves a complex network of polymorphic enzymes that may explain a proportion of the risk associated with colorectal neoplasia. Over 60 observational studies primarily in non-Hispanic White populations have been conducted on selected genetic variants in specific genes, MTHFR, MTR, MTRR, CBS, TCNII, RFC, GCPII, SHMT, TYMS, and MTHFD1, including five meta-analyses on MTHFR 677C>T (rs1801133) and MTHFR 1298C>T (rs1801131); two meta-analyses on MTR-2756A>C (rs1805087); and one for MTRR 66A>G (rs1801394). METHODS AND RESULTS This systematic review synthesizes these data, highlighting the consistent inverse association between MTHFR 677TT genotype and risk of colorectal cancer (CRC) and its null association with adenoma risk. Results for other variants varied across individual studies; in our meta-analyses we observed some evidence for SHMT 1420C>T (rs1979277) ((odds ratio) OR = 0.85; 95% confidence interval (CI) = 0.73-1.00 for TT v. CC) and TYMS 5' 28 bp repeat (rs34743033) and CRC risk (OR = 0.84; 95% CI = 0.75-0.94 for 2R/3R v. 3R/3R and OR = 0.82; 95% CI = 0.69-0.98 for 2R/2R v. 3R/3R). CONCLUSION To gain further insight into the role of folate variants in colorectal neoplasia will require incorporating measures of the metabolites, including B-vitamin cofactors, homocysteine and S-adenosylmethionine, and innovative statistical methods to better approximate the folate one-carbon metabolism pathway.
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Affiliation(s)
- Jane C Figueiredo
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Varela-Rey M, Woodhoo A, Martinez-Chantar ML, Mato JM, Lu SC. Alcohol, DNA methylation, and cancer. Alcohol Res 2013; 35:25-35. [PMID: 24313162 PMCID: PMC3860423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Cancer is one of the most significant diseases associated with chronic alcohol consumption, and chronic drinking is a strong risk factor for cancer, particularly of the upper aerodigestive tract, liver, colorectum, and breast. Several factors contribute to alcohol-induced cancer development (i.e., carcinogenesis), including the actions of acetaldehyde, the first and primary metabolite of ethanol, and oxidative stress. However, increasing evidence suggests that aberrant patterns of DNA methylation, an important epigenetic mechanism of transcriptional control, also could be part of the pathogenetic mechanisms that lead to alcohol-induced cancer development. The effects of alcohol on global and local DNA methylation patterns likely are mediated by its ability to interfere with the availability of the principal biological methyl donor, S-adenosylmethionine (SAMe), as well as pathways related to it. Several mechanisms may mediate the effects of alcohol on DNA methylation, including reduced folate levels and inhibition of key enzymes in one-carbon metabolism that ultimately lead to lower SAMe levels, as well as inhibition of activity and expression of enzymes involved in DNA methylation (i.e., DNA methyltransferases). Finally, variations (i.e., polymorphisms) of several genes involved in one-carbon metabolism also modulate the risk of alcohol-associated carcinogenesis.
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Frequent epigenetic silencing of the folate-metabolising gene cystathionine-beta-synthase in gastrointestinal cancer. PLoS One 2012; 7:e49683. [PMID: 23152928 PMCID: PMC3496708 DOI: 10.1371/journal.pone.0049683] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 10/11/2012] [Indexed: 12/31/2022] Open
Abstract
Background Both gastric and colorectal cancers (CRC) are the most frequently occurring malignancies worldwide with the overall survival of these patients remains unsatisfied. Identification of tumor suppressor genes (TSG) silenced by promoter CpG methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic biomarkers for early cancer detection and prognosis assessment. Cystathionine-beta-synthase (CBS) functions in the folate metabolism pathway, which is intricately linked to methylation of genomic DNA. Dysregulation of DNA methylation contributes substantially to cancer development. Methodology/Principal Findings To identify potential TSGs silenced by aberrant promoter methylation in CRC, we analyzed tumor and adjacent tissues from CRC cases using the Illumina Human Methylation45 BeadChip. We identified hypermethylation of the CBS gene in CRC samples, compared to adjacent tissues. Methylation and decreased mRNA expression of CBS were detected in most CRC cell lines by methylation-specific PCR and semiquantitative RT-PCR, as well as in gastric cancer. Treatment with 5-aza-2'-deoxycytidine and/or trichostatin A reversed methylation and restored CBS mRNA expression indicating a direct effect. Aberrant methylation was further detected in 31% of primary CRCs (29 of 96) and 55% of gastric tumors (11 of 20). In contrast, methylation was seldom found in normal tissues adjacent to the tumor. CBS methylation was associated with KRAS mutations in primary CRCs (P = 0.04, by χ2-test). However, no association was found between CBS methylation or KRAS mutations with cancer relapse/metastasis in Stage II CRC patients. Conclusion A novel finding from this study is that the folate metabolism enzyme CBS mRNA levels are frequently downregulated through CpG methylation of the CBS gene in gastric cancer and CRC, suggesting that CBS functions as a tumor suppressor gene. These findings warrant further study of CBS as an epigenetic biomarker for molecular diagnosis of gastrointestinal cancers.
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Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis. J Cancer Epidemiol 2012; 2012:952508. [PMID: 23125859 PMCID: PMC3483802 DOI: 10.1155/2012/952508] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 05/26/2012] [Accepted: 05/26/2012] [Indexed: 12/31/2022] Open
Abstract
Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms "folic acid," "folate," "colorectal cancer," "methylenetetrahydrofolate reductase," "MTHFR." Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95-1.10) and for 677TT versus CC was 0.88 (95% CI 0.80-0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56-0.89) and the 677TT genotype 0.63 (95% CI 0.41-0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes.
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Abstract
The risk of colorectal cancer (CRC) may be influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by impaired dietary folate intake as well as by polymorphic variants in one-carbon metabolism genes. A case-control study using seventy-one CRC patients and eighty unrelated healthy controls was carried out to assess the genetic association of fifteen SNP and one insertion in nine genes belonging to the folate pathway. Polymorphism selection was based on literature data, and included those which have a known or suspected functional impact on cancer and missense polymorphisms that are most likely to alter protein function. Genotyping was performed by real-time PCR and PCR followed by restriction analysis. The likelihood ratio statistic indicated that most of the polymorphisms were not associated with the risk of CRC. However, an increased risk of CRC was observed for two variant alleles of SNP mapping on the transcobalamin 2 gene (TCN2): C776G (rs1801198) and c.1026-394T>G (rs7286680). Considering the crucial biological function played by one-carbon metabolism genes, further investigations with larger cohorts of CRC patients are needed in order to confirm our preliminary results. These preliminary results indicate that TCN2 polymorphisms can be a susceptibility factor for CRC.
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Sheng X, Zhang Y, Zhao E, Lu S, Zheng X, Ge H, Lu W. MTHFR C677T polymorphism contributes to colorectal cancer susceptibility: evidence from 61 case-control studies. Mol Biol Rep 2012; 39:9669-79. [PMID: 22729883 DOI: 10.1007/s11033-012-1832-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 06/10/2012] [Indexed: 02/08/2023]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is believed to be involved in folate metabolism which plays a critical role in carcinogenesis. To date, many case-control studies have investigated the association between MTHFR C677T polymorphism and colorectal cancer risk. However, the results were inconsistent. In order to derive a more precise estimation of the association, we conducted this meta-analysis. This meta-analysis recruited 61 published studies which were selected by a search of PubMed up to 31st September 2011, including 16,111 colorectal cancer cases and 23,192 controls. We used crude odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association between MTHFR C677T polymorphism and colorectal cancer susceptibility. Our results showed that MTHFR C667T polymorphism contributed to the decreased colorectal cancer risk in overall population (for TT vs. CC: OR = 0.89, 95 % CI = 0.82-0.97; for TT vs. CT/CC: OR = 0.88, 95 % CI = 0.83-0.92). In subgroup analysis by ethnicity, the results also indicated a correlation between the T allele of MTHFR C667T and the colorectal cancer risk in Asian population (for TT vs. CC: OR = 0.82, 95 % CI = 0.69-0.97; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.74-0.90). Additionally, the correlation was also observed in male subgroup in sub-analysis by gender (for TT vs. CC: OR = 0.82, 95 % CI = 0.71-0.93; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.71-0.92). In summary, our meta-analysis strongly indicated the MTHFR C667T polymorphism was associated with a reduced risk of CRC.
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Affiliation(s)
- Xuewen Sheng
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
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Zhou D, Mei Q, Luo H, Tang B, Yu P. The polymorphisms in methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and the risk of colorectal cancer. Int J Biol Sci 2012; 8:819-30. [PMID: 22719222 PMCID: PMC3372886 DOI: 10.7150/ijbs.4462] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Accepted: 05/24/2012] [Indexed: 12/20/2022] Open
Abstract
Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.
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Affiliation(s)
- Daijun Zhou
- 4th team of Cadet Brigade, Third Military Medical University, Chongqing 400038, China
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31
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Han Y, Pan Y, Du Y, Tong N, Wang M, Zhang Z, Wan L, Wang L. Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms and Nonsyndromic Orofacial Clefts Susceptibility in a Southern Chinese Population. DNA Cell Biol 2011; 30:1063-8. [DOI: 10.1089/dna.2010.1185] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Yue Han
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Yongchu Pan
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Yifei Du
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Na Tong
- Department of Epidemiology, Nanjing Medical University, Nanjing, China
| | - Meilin Wang
- Department of Epidemiology, Nanjing Medical University, Nanjing, China
| | - Zhengdong Zhang
- Department of Epidemiology, Nanjing Medical University, Nanjing, China
| | - Linzhong Wan
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Lin Wang
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
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Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells, which transforms them into adenocarcinomas. Over the past decade, major advances have been made in understanding cancer epigenetics, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to have a functional role in CRC. The assessment of methylated genes in CRCs has also revealed a unique molecular subgroup of CRCs called CpG island methylator phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. These advances in our understanding of aberrant methylation in CRC have led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.
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Affiliation(s)
- Victoria Valinluck Lao
- Department of Surgery, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA,Department of Medicine, University of Washington Medical School, Seattle, WA
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Jokić M, Brčić-Kostić K, Stefulj J, Ivković TC, Božo L, Gamulin M, Kapitanović S. Association of MTHFR, MTR, MTRR, RFC1, and DHFR Gene Polymorphisms with Susceptibility to Sporadic Colon Cancer. DNA Cell Biol 2011; 30:771-6. [DOI: 10.1089/dna.2010.1189] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Mladen Jokić
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | | | - Jasminka Stefulj
- Laboratorie of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Tina Catela Ivković
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Lončar Božo
- Department of Surgery, Clinical Hospital Dubrava, Zagreb, Croatia
| | - Marija Gamulin
- Department of Oncology, Clinical Hospital Center Zagreb, Zagreb, Croatia
| | - Sanja Kapitanović
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
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Sameer AS, Shah ZA, Nissar S, Mudassar S, Siddiqi MA. Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population. GENETICS AND MOLECULAR RESEARCH 2011; 10:1200-10. [PMID: 21732284 DOI: 10.4238/vol10-2gmr1067] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C→T and 1298 A→C, have been shown to impact various diseases, including cancer. The 677 C→T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population.
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Affiliation(s)
- A S Sameer
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Kashmir, India
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35
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Gene polymorphisms involved in folate and methionine metabolism and increased risk of sporadic colorectal adenocarcinoma. Tumour Biol 2011; 32:853-61. [DOI: 10.1007/s13277-011-0185-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Accepted: 04/29/2011] [Indexed: 10/18/2022] Open
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Kang BS, Ahn DH, Kim NK, Kim JW. Relationship between Metabolic Syndrome and MTHFR Polymorphism in Colorectal Cancer. JOURNAL OF THE KOREAN SOCIETY OF COLOPROCTOLOGY 2011; 27:78-82. [PMID: 21602966 PMCID: PMC3092079 DOI: 10.3393/jksc.2011.27.2.78] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 04/18/2011] [Indexed: 10/26/2022]
Abstract
PURPOSE There have been studies on the relations between metabolic syndrome and colorectal cancer or on the relations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and colorectal cancer, but reports on the relationship between metabolic syndrome, MTHFR polymorphism and colorectal cancer all together are rare. The aim of this study is to find the interrelation between metabolic syndrome and MTHFR polymorphism in colorectal cancer. METHODS This study investigated 255 colorectal cancer patients (cancer group) who underwent surgery in our hospital from March 2003 to December 2008 and compared those patients to 488 healthy patients (control group). The diagnostic criterion for metabolic syndrome was based on the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III), and the MTHFR 677 polymorphism was analyzed. RESULTS When colorectal cancer patients and patients in the control group were classified as MTHFR 677 subtypes, there was no difference between the two groups: CC 87 (34.1%), CT 134 (52.6%), and TT 34 (13.3%) for the cancer group and CC 145 (32.4%), CT 238 (53.1%), and TT 65 (14.5%) for the control group. Distributions of MTHFR 677C/T genotype and allele frequencies in the individuals with and without metabolic syndrome in the cancer group showed no differences. Moreover, we could find no differences in distributions of MTHFR 677C/T genotypes in the clinical and the biomedical variables of individuals with and without metabolic syndrome in the cancer group. CONCLUSION Our results show no relation between metabolic syndrome and MTHFR polymorphism in colorectal cancer. However, a further prospective study, based on a precise diagnostic criterion for metabolic syndrome, is needed.
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Affiliation(s)
- Bong Su Kang
- Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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Ogino S, Chan AT, Fuchs CS, Giovannucci E. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut 2011; 60:397-411. [PMID: 21036793 PMCID: PMC3040598 DOI: 10.1136/gut.2010.217182] [Citation(s) in RCA: 450] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a complex disease resulting from somatic genetic and epigenetic alterations, including locus-specific CpG island methylation and global DNA or LINE-1 hypomethylation. Global molecular characteristics such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability cause alterations of gene function on a genome-wide scale. Activation of oncogenes including KRAS, BRAF and PIK3CA affects intracellular signalling pathways and has been associated with CIMP and MSI. Traditional epidemiology research has investigated various factors in relation to an overall risk of colon and/or rectal cancer. However, colorectal cancers comprise a heterogeneous group of diseases with different sets of genetic and epigenetic alterations. To better understand how a particular exposure influences the carcinogenic and pathologic process, somatic molecular changes and tumour biomarkers have been studied in relation to the exposure of interest. Moreover, an investigation of interactive effects of tumour molecular changes and the exposures of interest on tumour behaviour (prognosis or clinical outcome) can lead to a better understanding of tumour molecular changes, which may be prognostic or predictive tissue biomarkers. These new research efforts represent 'molecular pathologic epidemiology', which is a multidisciplinary field of investigations of the inter-relationship between exogenous and endogenous (eg, genetic) factors, tumoural molecular signatures and tumour progression. Furthermore, integrating genome-wide association studies (GWAS) with molecular pathological investigation is a promising area (GWAS-MPE approach). Examining the relationship between susceptibility alleles identified by GWAS and specific molecular alterations can help elucidate the function of these alleles and provide insights into whether susceptibility alleles are truly causal. Although there are challenges, molecular pathological epidemiology has unique strengths, and can provide insights into the pathogenic process and help optimise personalised prevention and therapy. In this review, we overview this relatively new field of research and discuss measures to overcome challenges and move this field forward.
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Affiliation(s)
- Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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Wallace K, Grau MV, Levine AJ, Shen L, Hamdan R, Chen X, Gui J, Haile RW, Barry EL, Ahnen D, McKeown-Eyssen G, Baron JA, Issa JPJ. Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa. Cancer Prev Res (Phila) 2010; 3:1552-64. [PMID: 21149331 PMCID: PMC3058541 DOI: 10.1158/1940-6207.capr-10-0047] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.
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Affiliation(s)
- Kristin Wallace
- Department of Medicine, Dartmouth Medical School, Evergreen Center, Lebanon, NH 03756, USA.
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Eussen SJPM, Vollset SE, Hustad S, Midttun Ø, Meyer K, Fredriksen A, Ueland PM, Jenab M, Slimani N, Boffetta P, Overvad K, Thorlacius-Ussing O, Tjønneland A, Olsen A, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, Weikert C, Pischon T, Linseisen J, Kaaks R, Trichopoulou A, Zilis D, Katsoulis M, Palli D, Pala V, Vineis P, Tumino R, Panico S, Peeters PHM, Bueno-de-Mesquita HB, van Duijnhoven FJB, Skeie G, Muñoz X, Martínez C, Dorronsoro M, Ardanaz E, Navarro C, Rodríguez L, VanGuelpen B, Palmqvist R, Manjer J, Ericson U, Bingham S, Khaw KT, Norat T, Riboli E. Plasma vitamins B2, B6, and B12, and related genetic variants as predictors of colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2010; 19:2549-61. [PMID: 20813848 PMCID: PMC3025315 DOI: 10.1158/1055-9965.epi-10-0407] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND B-vitamins are essential for one-carbon metabolism and have been linked to colorectal cancer. Although associations with folate have frequently been studied, studies on other plasma vitamins B2, B6, and B12 and colorectal cancer are scarce or inconclusive. METHODS We carried out a nested case-control study within the European Prospective Investigation into Cancer and Nutrition, including 1,365 incident colorectal cancer cases and 2,319 controls matched for study center, age, and sex. We measured the sum of B2 species riboflavin and flavin mononucleotide, and the sum of B6 species pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid as indicators for vitamin B2 and B6 status, as well as vitamin B12 in plasma samples collected at baseline. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for colorectal cancer were estimated using conditional logistic regression, adjusted for smoking, education, physical activity, body mass index, alcohol consumption, and intakes of fiber and red and processed meat. RESULTS The relative risks comparing highest to lowest quintile were 0.71 [95% confidence interval (95% CI), 0.56-0.91; P(trend) = 0.02] for vitamin B2, 0.68 (95% CI, 0.53-0.87; P(trend) <0.001) for vitamin B6, and 1.02 (95% CI, 0.80-1.29; P(trend) = 0.19) for vitamin B12. The associations for vitamin B6 were stronger in males who consumed ≥30 g alcohol/day. The polymorphisms were not associated with colorectal cancer. CONCLUSIONS Higher plasma concentrations of vitamins B2 and B6 are associated with a lower colorectal cancer risk. IMPACT This European population-based study is the first to indicate that vitamin B2 is inversely associated with colorectal cancer, and is in agreement with previously suggested inverse associations of vitamin B6 with colorectal cancer.
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Affiliation(s)
- Simone J P M Eussen
- LOCUS for homocysteine and related vitamins, Institute of Medicine, University of Bergen, and Haukeland University Hospital, Bergen, Norway.
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Wettergren Y, Odin E, Carlsson G, Gustavsson B. MTHFR, MTR, and MTRR polymorphisms in relation to p16INK4A hypermethylation in mucosa of patients with colorectal cancer. Mol Med 2010. [PMID: 20549016 DOI: 10.2119/molmed.2009-00156] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We recently analyzed the hypermethylation status of the p16INK4a (p16) gene promoter in normal-appearing mucosa obtained from patients with colorectal cancer. Hypermethylation of p16 was associated with reduced survival of these patients. In the present study, germ line polymorphisms in the folate- and methyl-associated genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR), were analyzed in the same patient cohort to find a possible link between these genetic variants and p16 hypermethylation. Genomic DNA was extracted from blood of patients (n = 181) and controls (n = 300). Genotype analyses were run on an ABI PRISM(®) 7900HT sequence-detection system (Applied Biosystems), using real-time polymerase chain reaction and TaqMan chemistry. The results showed that the genotype distributions of the patient and control groups were similar. No significant differences in cancer-specific or disease-free survival of stage I-III patients according to polymorphic variants were detected, nor were any differences in cancer-specific or disease-free survival detected when patients were subgrouped according to the MTHFR or MTR genotype groups and dichotomized by p16 hypermethylation status in mucosa. However, patients with the MTRR 66 AA/AG genotypes were found to have a significantly worse cancer-specific survival when the mucosa were positive, compared with negative, for p16 hypermethylation (hazard ratio 2.7; 95% confidence interval 1.2-6.4; P = 0.023). In contrast, there was no difference in survival among patients with the MTRR 66 GG genotype stratified by p16 hypermethylation status. These results indicate a relationship between genetic germ-line variants of the MTRR gene and p16 hypermethylation in mucosa, which may affect the clinical outcome of patients with colorectal cancer.
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Affiliation(s)
- Yvonne Wettergren
- Department of General Surgery, University of Gothenburg, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden.
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Wettergren Y, Odin E, Carlsson G, Gustavsson B. MTHFR, MTR, and MTRR polymorphisms in relation to p16INK4A hypermethylation in mucosa of patients with colorectal cancer. Mol Med 2010; 16:425-32. [PMID: 20549016 DOI: 10.2119/molmed.2009.00156] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Accepted: 06/10/2010] [Indexed: 12/17/2022] Open
Abstract
We recently analyzed the hypermethylation status of the p16INK4a (p16) gene promoter in normal-appearing mucosa obtained from patients with colorectal cancer. Hypermethylation of p16 was associated with reduced survival of these patients. In the present study, germ line polymorphisms in the folate- and methyl-associated genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR), were analyzed in the same patient cohort to find a possible link between these genetic variants and p16 hypermethylation. Genomic DNA was extracted from blood of patients (n = 181) and controls (n = 300). Genotype analyses were run on an ABI PRISM(®) 7900HT sequence-detection system (Applied Biosystems), using real-time polymerase chain reaction and TaqMan chemistry. The results showed that the genotype distributions of the patient and control groups were similar. No significant differences in cancer-specific or disease-free survival of stage I-III patients according to polymorphic variants were detected, nor were any differences in cancer-specific or disease-free survival detected when patients were subgrouped according to the MTHFR or MTR genotype groups and dichotomized by p16 hypermethylation status in mucosa. However, patients with the MTRR 66 AA/AG genotypes were found to have a significantly worse cancer-specific survival when the mucosa were positive, compared with negative, for p16 hypermethylation (hazard ratio 2.7; 95% confidence interval 1.2-6.4; P = 0.023). In contrast, there was no difference in survival among patients with the MTRR 66 GG genotype stratified by p16 hypermethylation status. These results indicate a relationship between genetic germ-line variants of the MTRR gene and p16 hypermethylation in mucosa, which may affect the clinical outcome of patients with colorectal cancer.
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Affiliation(s)
- Yvonne Wettergren
- Department of General Surgery, University of Gothenburg, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden.
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Cui LH, Shin MH, Kweon SS, Kim HN, Song HR, Piao JM, Choi JS, Shim HJ, Hwang JE, Kim HR, Park YK, Kim SH. Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population. BMC Cancer 2010; 10:236. [PMID: 20504332 PMCID: PMC2893109 DOI: 10.1186/1471-2407-10-236] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Accepted: 05/26/2010] [Indexed: 12/17/2022] Open
Abstract
Background This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population. Methods We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer. Conclusions The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.
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Affiliation(s)
- Lian-Hua Cui
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea
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Chang SC, Lin PC, Yang SH, Wang HS, Liang WY, Lin JK. Taiwan hospital-based detection of Lynch syndrome distinguishes 2 types of microsatellite instabilities in colorectal cancers. Surgery 2010; 147:720-8. [DOI: 10.1016/j.surg.2009.10.069] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2009] [Accepted: 10/30/2009] [Indexed: 11/27/2022]
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Levine AJ, Figueiredo JC, Lee W, Poynter JN, Conti D, Duggan DJ, Campbell PT, Newcomb P, Martinez ME, Hopper JL, Le Marchand L, Baron JA, Limburg PJ, Ulrich CM, Haile RW. Genetic variability in the MTHFR gene and colorectal cancer risk using the colorectal cancer family registry. Cancer Epidemiol Biomarkers Prev 2010; 19:89-100. [PMID: 20056627 DOI: 10.1158/1055-9965.epi-09-0727] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The MTHFR C677T TT genotype is associated with a 15% to 18% reduction in colorectal cancer risk, but it is not clear if other variants of the gene are associated with colorectal cancer risk. METHODS We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and colorectal cancer risk using a large family-based case-control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry. We assessed 22 TagSNPs, selected based on pairwise r(2) >95%, using the Haploview Tagger and genotyped the TagSNPs on the Illumina GoldenGate or Sequenom platforms. The association between single nucleotide polymorphisms and colorectal cancer was assessed using log-additive, codominant, and recessive models. RESULTS From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased colorectal cancer risk overall [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.63-1.04; and OR, 0.82; 95% CI, 0.64-1.07, respectively]. The 677 TT genotype was associated with a decreased risk of microsatellite-stable/microsatellite-low tumors (OR, 0.69; 95% CI, 0.49-0.97) and an increased risk of microsatellite-high tumors (OR, 2.22; 95% CI, 0.91-5.43; P(interaction) = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (P(interaction) = 0.02). No other single nucleotide polymorphism was associated with risk overall or within subgroups. CONCLUSION The 677 TT and 1298 CC genotypes may each be associated with a decrease in colorectal cancer risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to colorectal cancer risk.
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Affiliation(s)
- A Joan Levine
- USC Keck School of Medicine, Department of Preventive Medicine, Genetic Epidemiology, NRT 1450 Biggy Street, Room 1509A, Los Angeles, CA 90033, USA.
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PELLEGRINI M, ARGIBAY P, GOMEZ D. Dietary factors, genetic and epigenetic influences in colorectal cancer. Exp Ther Med 2010; 1:241-250. [PMID: 22993535 PMCID: PMC3445943 DOI: 10.3892/etm_00000038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 11/10/2009] [Indexed: 01/05/2023] Open
Abstract
Genetic influences, together with epigenetic components and dietary factors, play a fundamental role in the initiation and progression of cancer by causing a number of deregulations. Colorectal cancer (CRC) is a disease influenced by dietary factors, for which established genetic and epigenetic alterations have been identified. Within CRC, there are hereditary syndromes that present mutations in the germ-line hMLH1, and also alterations in the methylation of the promoters. Epigenetics has also been established as a pathway of carcinogenesis. In the present review, we analyzed studies conducted to discern the different pathways leading to established CRC, stressing the importance of identifying factors that may predict CRC at an early stage, since it is mostly a silent disease observed at the clinical level in advanced stages.
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Affiliation(s)
- M.L. PELLEGRINI
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires
| | - P. ARGIBAY
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires
| | - D.E. GOMEZ
- Laboratorio de Oncología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Buenos Aires,
Argentina
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Naghibalhossaini F, Mokarram P, Khalili I, Vasei M, Hosseini SV, Ashktorab H, Rasti M, Abdollahi K. MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients. CANCER GENETICS AND CYTOGENETICS 2010; 197:142-51. [PMID: 20193847 PMCID: PMC3684801 DOI: 10.1016/j.cancergencyto.2009.11.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Revised: 11/02/2009] [Accepted: 11/19/2009] [Indexed: 11/29/2022]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. We aimed to test the hypothesis that C677T and A1298C variants of MTHFR predispose to microsatellite instable (MSI) colorectal cancer. We determined MTHFR genotypes in 175 sporadic colorectal cancer patients and a total of 231 normal controls in Shiraz, Southern Iran. Among the genotypes found in our samples, MTHFR CT and CT+TT were associated with increased risk for CRC incidence [odds ratio (OR)=2.4, 95% confidence interval (95%CI)=1.8-4.4; OR=2.4, 95%CI=1.6-3.6, respectively]. Double heterozygotes 677CT/1298AC and double homozygote 677TT/1298AA and 677CC/1298CC genotypes also showed a significantly increased risk of developing CRC compared with the wild-type 677CC/1298AA genotypes of the controls. Among the 151 tumors tested, 36 (23.8%) were MSI+. MSI was more common in proximal tumors (OR=10.4; 95%CI=3.9-27.8) and in smokers (OR=2.9; 95%CI=1.3-6.7). In a case-control comparison, the MTHFR 677CT+TT genotype was strongly associated with MSI (OR=2.6; 95%CI=1.3-5.3). Hypermethylation of mismatch repair genes was positively related with MSI incidence in these tumor series (P=0.00). Our data suggest that the MTHFR 677CT+TT variant genotype may be a risk factor for MSI+ cancer.
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Affiliation(s)
- Fakhraddin Naghibalhossaini
- Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Zand Street, Shiraz, Fars, Iran. <>
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Fernández-Peralta AM, Daimiel L, Nejda N, Iglesias D, Medina Arana V, González-Aguilera JJ. Association of polymorphisms MTHFR C677T and A1298C with risk of colorectal cancer, genetic and epigenetic characteristic of tumors, and response to chemotherapy. Int J Colorectal Dis 2010; 25:141-51. [PMID: 19669769 DOI: 10.1007/s00384-009-0779-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The enzyme MTHFR plays an important role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair, and synthesis. We analyze the relationship of MTHFR C677T and A1298C polymorphisms with biological, clinicopathological, genetic and epigenetic features of tumors, and the patient outcome after treatment with 5-FU-based chemotherapy to determine the contribution of MTHFR genotypes in the risk of colorectal cancer (CRC) and in the response to therapy. METHODS Genomic DNA of 143 Spanish sporadic CRC and 103 controls was analyzed by polymerase chain reaction/restriction fragment length polymorphism and sequencing. RESULTS The C677T polymorphism has protective effect on CRC showing TT genotype an odds ratios of 0.06 (95% confidence interval (CI): 0.10-0.32) and the CT of 0.51 (95% CI: 0.3-0.87). MTHFR A1298C polymorphism is not associated with CRC risk. Patients with 1298CC and AC genotypes exhibit worse survival than those with the wild genotype (log rank, p = 0.001), whereas C677T genotypes do not affect patient survival (log rank, p = 0.92). MTHFR 677T allele carriers responded better to 5-FU-based chemotherapy than patients with the wild CC genotype (log rank, p = 0.05). The variant C allele of A1298C affects negatively the response to 5-FU-based chemotherapy (log rank, p = 0.009). CONCLUSIONS The variant allele of the C677T has a protective effect on CRC development, whereas the variant allele of the A1298C does not produce any effect on disease risk. Both MTHFR polymorphisms are relevant and independent factors of patient outcome after 5FU-based treatment of CRC, and MTHFR genotyping may be of predictive benefit in selecting treatment regimens.
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Affiliation(s)
- Antonia M Fernández-Peralta
- Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
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Manne U, Shanmugam C, Katkoori VR, Bumpers HL, Grizzle WE. Development and progression of colorectal neoplasia. Cancer Biomark 2010; 9:235-65. [PMID: 22112479 PMCID: PMC3445039 DOI: 10.3233/cbm-2011-0160] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A variety of genetic and molecular alterations underlie the development and progression of colorectal neoplasia (CRN). Most of these cancers arise sporadically due to multiple somatic mutations and genetic instability. Genetic instability includes chromosomal instability (CIN) and microsatellite instability (MSI), which is observed in most hereditary non-polyposis colon cancers (HNPCCs) and accounts for a small proportion of sporadic CRN. Although many biomarkers have been used in the diagnosis and prediction of the clinical outcomes of CRNs, no single marker has established value. New markers and genes associated with the development and progression of CRNs are being discovered at an accelerated rate. CRN is a heterogeneous disease, especially with respect to the anatomic location of the tumor, race/ethnicity differences, and genetic and dietary interactions that influence its development and progression and act as confounders. Hence, efforts related to biomarker discovery should focus on identification of individual differences based on tumor stage, tumor anatomic location, and race/ethnicity; on the discovery of molecules (genes, mRNA transcripts, and proteins) relevant to these differences; and on development of therapeutic approaches to target these molecules in developing personalized medicine. Such strategies have the potential of reducing the personal and socio-economic burden of CRNs. Here, we systematically review molecular and other pathologic features as they relate to the development, early detection, diagnosis, prognosis, progression, and prevention of CRNs, especially colorectal cancers (CRCs).
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Affiliation(s)
- Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Abstract
Invasive tumors (cancers or malignant lesions) typically develop in the setting in which there is the presence of putative non-invasive lesions and the development of these non-invasive lesions frequently precedes the development of cancers. For some organs, such as the oral cavity, cervix and skin, the respective putative pre-invasive lesions can be observed over time and documented to progress to invasive lesions. However, for less readily observable lesions, such as those of the prostate, the progression of the pre-invasive lesions, e.g., prostatic intraepithelial neoplasia (PIN) and prostatic proliferative inflammatory atrophy (PIA) to prostatic cancer are more difficult to document. Thus, for most organ systems, specific pre-invasive neoplastic lesions have been proposed based upon the apparent observations of one or more of the following: 1) microinvasive disease developing from a pre-invasive neoplastic lesion, 2) the general association of the pre-invasive lesion with invasive lesions, 3) the subsequent development of invasive lesions following diagnosis of the pre-invasive lesion, 4) correlations of the molecular features of the putative pre-invasive lesion with the matching invasive lesions, and 5) reductions in the rate of cancer following removal of the pre-invasive lesion. When there are mixtures of pre-invasive lesions with actual cancers in the same case, some of the above specific associations are more difficult to make. Several terms have been used to describe pre-invasive lesions, many of which are now less useful as our knowledge of these lesions increases. It is now commonly accepted that these lesions are a features of the spectrum of neoplastic development and most are accepted as ``neoplastic lesions'' with associated molecular features, even though they may be reversible even if they have mutations in suppressor genes (e.g., p53) or are associated with viral etiologies (e.g., cervical intraepithelial neoplasia). The overall term, "pre-invasive neoplasia", seems to best describe these putative pre-invasive lesions. Thus, terms such as incipient neoplasia should be abandoned. The term "intra-epithelial neoplasia" with an associated grade, which has been developed for pre-invasive neoplastic lesions of the cervix, i.e. cervical intraepithelial neoplasia (CIN), seems to be a terminology that adds consistency across epithelial organs. Thus, adoption of these terms for the additional organ sites of pancreas (PanIN) and prostate (PIN) seems accepted. Less descriptive terms such as the degrees of dysplasia of the oral cavity and bronchopulmonary system and actinic keratosis and Bowen's disease of the skin might be better designated as oral intraepithelial neoplasia (OIN), pulmonary intraepithelial neoplasia (PulIN) and dermal intraepithelial neoplasia (DIN). The etiology of pre-invasive neoplasia is the etiology of the matching cancers. Some obvious initiating factors include exposure to the whole range of ionizing and non-ionizing radiation, tobacco abuse and a broad range of other carcinogens (e.g., benzene). A frequent initiation factor is the setting of long standing continuing damage, inflammation and repair (LOCDIR) which leads to early molecular features associated with neoplasia after about one year. An excellent example of this is ulcerative colitis (UC) in which dysregulation of microsatellite repair enzymes have been documented one year following diagnosis of UC. While the nomenclature, description, diagnosis and etiology of pre-invasive neoplasia has advanced, approaches to therapy of such lesions have not progressed adequately even though it has been identified that, for example, removal of polyps periodically from the colorectum, DCIS from the breast, and high grade CIN from the cervix, results in a reduction in the development of cancers of the colorectum, breast, and cervix, respectively. With the development of more molecularly targeted therapy with fewer side effects, preventive therapies may be more successfully targeted to pre-invasive neoplastic lesions.
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Affiliation(s)
- William E Grizzle
- Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Golimbet V, Korovaitseva G, Abramova L, Kaleda V. The 844ins68 polymorphism of the cystathionine beta-synthase gene is associated with schizophrenia. Psychiatry Res 2009; 170:168-71. [PMID: 19906435 DOI: 10.1016/j.psychres.2008.07.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2007] [Revised: 05/30/2008] [Accepted: 07/20/2008] [Indexed: 11/26/2022]
Abstract
A subtle genetic defect in homocysteine metabolism is thought to play an etiologic role in schizophrenia. Cystathionine-beta-synthase (CBS) is a key enzyme related to homocysteine levels. The aim of the present study was to search for association between the 844ins68 polymorphism of the CBS gene and schizophrenia in a large Russian sample using case-control and family-based designs. The sample comprised 1135 patients, 626 controls and 172 families. There was a trend for association between the 844ins68 polymorphism and schizophrenia in the case-control study, with higher frequency of the insertion in the control group. The FBAT revealed a statistically significant difference in transmission of alleles from parents to the affected proband, with preferential transmission of the variant without insertion. When the sample of patients was stratified by sex and forms of schizophrenia, the significantly lower frequency of insertion was observed in the group of female patients with chronic schizophrenia (n=180) as compared to psychiatrically well women. The insertion variant has been reported earlier to be related to decreased levels of homocysteine and thus thought to play a protective role. In conclusion, our study revealed a possible relation of the CBS 844ins68 polymorphism to schizophrenia.
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Affiliation(s)
- Vera Golimbet
- Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
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