MTHFR C677T and A1298C polymorphism's effect on risk of colorectal cancer in Lynch syndrome.

Autor: Wiik MU; Research Unit, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund, Norway.; Department of Medicine, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund, Norway.; Department of Biological Sciences, Faculty of Natural Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Negline M; School of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia., Beisvåg V; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway.; St. Olav's University Hospital, Central Staff, 7006, Trondheim, Norway., Clapham M; School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia., Holliday E; School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia., Dueñas N; Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Brunet J; Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Pineda M; Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Bonifaci N; Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Aretz S; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.; Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany., Klinkhammer H; Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany.; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany., Spier I; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.; Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany., Perne C; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany., Mayr A; Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany., Valle L; Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Lubinski J; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland., Sjursen W; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway.; Department of Medical Genetics, St Olavs University Hospital, Trondheim, Norway., Scott RJ; School of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.; Department of Molecular Genetics, NSW Health Pathology, John Hunter Hospital, Newcastle, NSW, Australia., Talseth-Palmer BA; Research Unit, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund, Norway. bente.talseth-palmer@newcastle.edu.au.; School of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia. bente.talseth-palmer@newcastle.edu.au.; NSW Health Pathology, Newcastle, NSW, Australia. bente.talseth-palmer@newcastle.edu.au.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Nov 01; Vol. 13 (1), pp. 18783. Date of Electronic Publication: 2023 Nov 01.
DOI: 10.1038/s41598-023-44120-8
Abstrakt: Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10-80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.
(© 2023. Crown.)
Databáze: MEDLINE
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