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Single-nucleotide polymorphisms (SNPs), variations at a single base position, have been identified in both protein-coding and noncoding DNA sequences, but the vast majority of millions of those variants are far from being functionally understood. Here we show that a common variant in the gene MTHFR [rs1801133 (C>T)] not only influences response to neoadjuvant chemoradiotherapy in patients with rectal cancer, but it also influences recurrence of the disease itself. More specifically, patients with the homozygous ancestral (wild type) genotype (C/C) were 2.91 times more likely (291% increased benefit) to respond to neoadjuvant chemoradiotherapy {95% CI: [1.23, 6.89]; P=0.0150} and 3.25 times more likely (325% increased benefit) not to experience recurrence of the disease {95% CI: [1.37, 7.72]; P=0.0079} than patients with either the heterozygous (C/T) or the homozygous mutation (T/T) genotype. These results identify MTHFR as an important genetic marker and open up new, pharmacogenomic strategies in the treatment and management of rectal cancer.","authorString":"Jason B Nikas, Janet T Lee, Elizabeth D Maring, Jill Washechek-Aletto, Donna Felmlee-Devine, Ruth A Johnson, Thomas C Smyrk, Patrick S Tawadros, Lisa A Boardman, Clifford J Steer","citation":"Nikas et al., 2015","citationId":"26693073","id":1221,"journal":"Am J Cancer Res","link":"/sources/1221","name":"PubMed: Nikas et al., 2015","openAccess":true,"pmcId":"PMC4656744","publicationDate":"2015","retracted":false,"sourceType":"PUBMED","sourceUrl":"http://www.ncbi.nlm.nih.gov/pubmed/26693073","title":"A common variant in MTHFR influences response to chemoradiotherapy and recurrence of rectal cancer."},"therapies":[{"deprecated":false,"id":420,"link":"/therapies/420","name":"Fluorouracil"}],"variantOrigin":"COMMON_GERMLINE"},{"description":"The MTHFR C667T variant was associated with significantly lower relapse-free survival and overall survival in stomach cancer patients treated with 5-Fluorouracil-based therapies. 116 Chinese patients with histologically confirmed gastric cancer were used in this study, and all patients had radical surgery before treatment.","disease":{"diseaseAliases":["Gastric Cancer","Gastric Neoplasm"],"diseaseUrl":"https://www.disease-ontology.org/?id=DOID:10534","displayName":"Stomach Cancer","doid":"10534","id":21,"link":"/diseases/21","myDiseaseInfo":{"doDef":"A gastrointestinal system cancer that is located_in the stomach.","icd10":"[\"C16\", \"C16.2\", \"C16.5\", \"C16.6\"]","mesh":"D013274","mondoId":"MONDO:0001056","ncit":["C3387","C9331"]},"name":"Stomach Cancer"},"evidenceDirection":"SUPPORTS","evidenceLevel":"B","evidenceRating":3,"evidenceType":"PREDICTIVE","flagged":false,"id":669,"molecularProfile":{"id":254},"name":"EID669","significance":"SENSITIVITYRESPONSE","source":{"abstract":"The aim of this study was to investigate the association of the thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms with the clinical outcomes of gastric cancer patients treated with 5-FU-based adjuvant chemotherapy.One-hundred and sixteen patients with gastric cancer were treated with 5-FU-based adjuvant chemotherapy. The TS (a 28-bp tandem repeat polymorphism in the TS enhancer region (TSER) and a 6 bp deletion/insertion polymorphism in the 3'-untranslated region) and MTHFR C677T polymorphisms were determined in blood samples from those patients using PCR and PCR-LDR (ligation detection reaction) method, respectively.The overall survival (OS) in patients with the TS ins6/ins6 genotype was significantly shorter than those in patients with the del6/del6 (P = 0.017) and ins6/del6 (P = 0.022) genotype. The relapse-free survival (RFS) and OS in patients with the MTHFR C/C genotype were significantly worse than those in patients with the T/T or C/T genotype (P = 0.043 and 0.040, respectively). Cox multivariate analysis also showed that patients with the TS ins6/ins6 genotype have worse OS than patients with the T/T or C/T genotype (HR = 2.437, P = 0.041), and the MTHFR C/C genotype was associated with shorter RFS (HR = 1.723, P = 0.031) and OS (HR = 1.681, P = 0.056). No significant association was found between the TSER polymorphism and the clinical outcomes (P > 0.05).The polymorphisms of TS 3'-UTR ins6/del6 and MTHFR C677T appear to be potential prognostic factors in gastric cancer patients treated with 5-FU-based adjuvant chemotherapy, which may allow identification of gastric cancer patients who will benefit from 5-FU chemotherapy.","authorString":"Zhao-Hui Huang, Dong Hua, Li-Hua Li","citation":"Huang et al., 2009","citationId":"18704422","id":424,"journal":"Cancer Chemother Pharmacol","link":"/sources/424","name":"PubMed: Huang et al., 2009","openAccess":false,"publicationDate":"2009-4","retracted":false,"sourceType":"PUBMED","sourceUrl":"http://www.ncbi.nlm.nih.gov/pubmed/18704422","title":"The polymorphisms of TS and MTHFR predict survival of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population."},"therapies":[{"deprecated":false,"id":420,"link":"/therapies/420","name":"Fluorouracil"}],"variantOrigin":"COMMON_GERMLINE"},{"description":"Study of 1817 PCa cases and 2026 cancer free controls to clarify the association of (MTHFR)c.677C>T (and c.1298A>C ) of pancreatic cancer risk in a population of Han Chinese in Shanghai. Results indicated a lower risk for the heterozygous CT genotype and homozygous TT genotype carriers of (MTHFR)c.677C>T which had a significantly lower risk of developing pancreatic cancer compared with the wild-type CC genotype.","disease":{"diseaseAliases":["Ca Body Of Pancreas","Ca Head Of Pancreas","Ca Tail Of Pancreas","Malignant Neoplasm Of Body Of Pancreas","Malignant Neoplasm Of Head Of Pancreas","Malignant Neoplasm Of Tail Of Pancreas","Pancreas Neoplasm","Pancreatic Neoplasm","Pancreatic Tumor"],"diseaseUrl":"https://www.disease-ontology.org/?id=DOID:1793","displayName":"Pancreatic Cancer","doid":"1793","id":556,"link":"/diseases/556","myDiseaseInfo":{"doDef":"An endocrine gland cancer located_in the pancreas.","icd10":"[\"C25.0\", \"C25.1\", \"C25.2\"]","mesh":"D010190","mondoId":"MONDO:0009831","ncit":["C3305"]},"name":"Pancreatic Cancer"},"evidenceDirection":"SUPPORTS","evidenceLevel":"B","evidenceRating":4,"evidenceType":"PREDISPOSING","flagged":false,"id":1756,"molecularProfile":{"id":254},"name":"EID1756","significance":"PROTECTIVENESS","source":{"abstract":"Methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C variants were known to be associated with prostate cancer (PCa) risk with conflicting results, because of MTHFR and nutrient status interaction in the prostate development. In this large-scale, hospital-based, case-control study of 1817 PCa cases and 2026 cancer-free controls, we aimed to clarify the association between these two MTHFR variants and PCa risk in Shanghai and to explore the underlying molecular mechanisms. We found that both the heterozygous CT (adjusted OR = 0.78, 95% CI: 0.67-0.92) and the homozygous TT genotypes (adjusted OR = 0.68, 95% CI: 0.55-0.83) of c.677C>T were associated with a significantly decreased risk of PCa compared with homozygous wild-type CC genotype, respectively, using multivariate logistic regression. Furthermore, we confirmed that MTHFR c.677T allele was related to an increased serum homocysteine level in the Han Chinese population in Shanghai. In the cultured PCa cell lines, we observed that MTHFR c.677T could elevate the cellular homocysteine level and cause DNA damage, thus increasing cell apoptosis and finally inhibiting cell proliferation. In conclusion, MTHFR c.677T was a protective factor of PCa risk in ethnic Han Chinese males by inducing DNA damage and cell apoptosis.","authorString":"Jun-Long Wu, Shu-Xian Zhou, Rui Zhao, Xuan Zhang, Kun Chang, Cheng-Yuan Gu, Hua-Lei Gan, Bo Dai, Yao Zhu, Hai-Liang Zhang, Guo-Hai Shi, Yuan-Yuan Qu, Jian-Yuan Zhao, Ding-Wei Ye","citation":"Wu et al., 2016","citationId":"27819322","id":1218,"journal":"Sci Rep","link":"/sources/1218","name":"PubMed: Wu et al., 2016","openAccess":true,"pmcId":"PMC5098242","publicationDate":"2016-11-7","retracted":false,"sourceType":"PUBMED","sourceUrl":"http://www.ncbi.nlm.nih.gov/pubmed/27819322","title":"MTHFR c.677C>T Inhibits Cell Proliferation and Decreases Prostate Cancer Susceptibility in the Han Chinese Population in Shanghai."},"variantOrigin":"COMMON_GERMLINE"}],"id":254,"molecularProfileAliases":["RS1801133","C677T","ALA222VAL"],"molecularProfileScore":55.0,"name":"MTHFR 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blood","pmid":21829388,"snpid":"rs1801133","title":"Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex"},{"date_pub":"8/4/2011","journal":"PLoS Genet","location_within_paper":"TableS3","p_value":1.1e-15,"paper_phenotype_categories":"Quantitative trait(s);Gene expression (RNA);Blood-related","paper_phenotype_description":"Gene expression in blood cells","phenotype":"Gene expression of MTHFR///AL953897.6 in blood","pmid":21829388,"snpid":"rs1801133","title":"Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex"},{"date_pub":"8/4/2011","journal":"PLoS Genet","location_within_paper":"TableS3","p_value":1.5e-25,"paper_phenotype_categories":"Quantitative trait(s);Gene expression (RNA);Blood-related","paper_phenotype_description":"Gene expression in blood cells","phenotype":"Gene expression of MFN2 in blood","pmid":21829388,"snpid":"rs1801133","title":"Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex"},{"date_pub":"8/4/2011","journal":"PLoS Genet","location_within_paper":"TableS3","p_value":1.7e-19,"paper_phenotype_categories":"Quantitative trait(s);Gene expression (RNA);Blood-related","paper_phenotype_description":"Gene expression in blood cells","phenotype":"Gene expression of PLOD1 in blood","pmid":21829388,"snpid":"rs1801133","title":"Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex"},{"date_pub":"9/11/2011","journal":"Nature","location_within_paper":"Full Data","p_value":0.0138,"paper_phenotype_categories":"Quantitative trait(s);Blood pressure;CVD risk factor (CVD RF)","paper_phenotype_description":"Blood pressure","phenotype":"Diastolic blood pressure (DBP)","pmid":21909115,"snpid":"rs1801133","title":"Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk."},{"date_pub":"10/30/2011","journal":"Nat Genet","location_within_paper":"Table 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