Polymorphisms in methyl-group metabolism genes and risk of sporadic colorectal cancer with relation to the CpG island methylator phenotype |
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| Authors: | Pawel Karpinski Aleksander Myszka David Ramsey Blazej Misiak Justyna Gil Izabela Laczmanska Zygmunt Grzebieniak Tadeusz Sebzda Robert Smigiel Agnieszka Stembalska Maria M Sasiadek |
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| Institution: | 1. Department of Genetics, Wroclaw Medical University, ul. Marcinkowskiego 1, 50-368 Wroclaw, Poland;2. Department of Genetics, University of Rzeszow, Rzeszow, Poland;3. Department of Statistics and Mathematics, University of Limerick, Plassey, Limerick, Ireland;4. 2nd Department of General and Oncological Surgery, Wroclaw Medical University, Poland;5. Department of Pathophysiology, Wroclaw Medical University, Poland;1. School of Computer, Science and Technology, Tianjin University, Tianjin, China;2. Institute of Applied Mathematics, Hebei Academy of Sciences, Shijiazhuang, China;3. School of Electronic Information Engineering, Tianjin University, Tianjin, China;4. Department of Automation, North China Electric Power University, Baoding 071003, Hebei Province, China;5. Knowledge Engineering and Discovery Research Institute, Auckland University of Technology, Auckland 1010, New Zealand;6. Hebei Authentication Technology Engineering Research Center, Shijiazhuang, China;1. Demonstration Laboratory of Proteomic Research, Laboratory Centre of Life Science, College of Life Science, Nanjing Agricultural University, Nanjing 210095, China;2. State Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences, Nanjing 210008, China;3. College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China;1. Department of Public Health Sciences, Queen’s University, Kingston, Ontario K7L3N6, Canada;2. Department of Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2R3, Canada;3. Gastrointestinal Diseases Research Unit (GIDRU), Queen’s University, Kingston, Ontario K7L3N6, Canada;1. Third Department of Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, 050011, China;2. Department of General Surgery, Hebei General Hospital, Shijiazhuang, 050051, China;3. Department of Pathology, PLA Bethune International Peace Hospital, Shijiazhuang, 050000, China;1. Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China;2. The Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China;3. Bank of Blood Products, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China;4. Department of Neurosurgery, Ningbo First Hospital, Ningbo University, Ningbo, Zhejiang 315010, China;1. University Medical Centre Utrecht, Department of Radiation Oncology, The Netherlands;2. Academic Medical Centre, Department of Radiotherapy, Amsterdam, The Netherlands |
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| Abstract: | Background: The CpG island methylator phenotype (CIMP), together with extensive promoter methylation, is regarded as one of the mechanisms involved in colorectal carcinogenesis. The mechanisms underlying CIMP in sporadic colorectal cancer are poorly understood. Genes involved in methyl-group metabolism are likely to affect DNA methylation and thereby influence an individual's risk of CIMP. The aim of the present study was to evaluate whether polymorphisms in the genes encoding methyl-group metabolism pathway predispose to CIMP+ and/or CIMP? CRC. Methods: We examined the potential association between the polymorphisms of MTHFR 677C>T, TS 5′UTR 2R/3R, TS 3′UTR 1494del6, ΔDNMT3B ?149C>T and DNMT3B ?283T>C in a group of 46 CIMP+ CRC cases, 140 CIMP? CRC cases and 140 healthy controls. The CIMP status of the CRC cases was determined by MS-PCR in tumor tissue by a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), which was also followed by analyzing hMLH1 methylation and BRAF V600E mutation. Results: The variant allele homozygote genotype for the ΔDNMT3B ?283T>C polymorphism was associated with a decreased risk for CIMP+ CRC (OR: 0.31, 95%CI: 0.09–0.73, p = 0.009). Individuals with TS 3R/3R had an increased risk of CIMP? CRC (OR: 2.21, 95%CI: 1.23–4.91, p = 0.01). Moreover, the carriers of 3R allele had an increased risk of CIMP? CRC (OR: 1.45, 95%CI: 1.10–2.13, p = 0.01). Conclusion: This study provides support to the hypothesis that methyl-group metabolism plays a role in the etiology of both CIMP+ and CIMP? colorectal cancers but has a different impact on a distinct molecular subgroups of colorectal cancer. |
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