title: The RFC1 80G>A, among Common One-Carbon Polymorphisms, Relates to Survival Rate According to DNA Global Methylation in Primary Liver Cancers.
abstract: Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low (≤5.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (p<0.0001) with a higher Hazard Ratio (HR = 6.62, p = 0.001). The subjects carrying the AA genotype in association with high mCyt did not show a significant difference in survival rate as compared with the G allele carriers (p = 0.919). The RFC1 80G>A polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers.
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Moruzzi
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Udali
authors.affiliation: Department of Surgery, University of Verona School of Medicine, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruzzenente
authors.affiliation: Department of Surgery, University of Verona School of Medicine, Verona, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Guglielmi
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Guarini
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Martinelli
authors.affiliation: Department of Surgery, University of Verona School of Medicine, Verona, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Conci
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Mazzi
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pattini
authors.affiliation: Tufts University School of Nutrition Science and Policy, Boston, Massachusetts, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Tammen
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Oliviero
authors.initials: O
authors.lastname: Olivieri
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pizzolo
authors.affiliation: Tufts University School of Nutrition Science and Policy, Boston, Massachusetts, United States of America.|Chaum Life Center, CHA University, Seoul, Korea.
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Simonetta
authors.identifier: http://orcid.org/0000-0002-9606-6711
authors.initials: S
authors.lastname: Friso
mesh_terms: D000368:Aged; D002244:Carbon / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D019175:DNA Methylation; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods / Q000706:statistics & numerical data; D015996:Survival Rate
chemical_list: D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D002244:Carbon