title: Variation within 3'-UTRs of base excision repair genes and response to therapy in colorectal cancer patients: A potential modulation of microRNAs binding.
abstract: OBJECTIVE
  Colorectal cancer is routinely treated with a 5-fluorouracil (5-FU)-based chemotherapy. 5-FU incorporates into DNA, and the base excision repair (BER) pathway specifically recognizes such damage. We investigated the association of single-nucleotide polymorphisms (SNP) in the 3'-untranslated regions (UTR) of BER genes, and potentially affecting the microRNA (miRNA) binding, on the risk of colorectal cancer, its progression, and prognosis. SNPs in miRNA-binding sites may modulate the posttranscriptional regulation of gene expression operated by miRNAs and explain interindividual variability in BER capacity and response to 5-FU.
  
  
  METHODS
  We tested 12 SNPs in the 3'-UTRs of five BER genes for colorectal cancer susceptibility in a case-control study (1,098 cases and 1,459 healthy controls). Subsequently, we analyzed the role of these SNPs on clinical outcomes of patients (866 in the Training set and 232 in the Replication set).
  
  
  RESULTS
  SNPs in the SMUG1 and NEIL2 genes were associated with overall survival. In particular, SMUG1 rs2233921 TT carriers showed increased survival compared with those with GT/GG genotypes [HR, 0.54; 95% confidence interval (CI), 0.36-0.81; P = 0.003] in the Training set and after pooling results from the Replication set. The association was more significant following stratification for 5-FU-based chemotherapy (P = 5.6 × 10(-5)). A reduced expression of the reporter gene for the T allele of rs2233921 was observed when compared with the common G allele by in vitro assay. None of the genotyped BER polymorphisms were associated with colorectal cancer risk.
  
  
  CONCLUSIONS
  We provide the first evidence that variations in miRNA-binding sites in BER genes 3'-UTR may modulate colorectal cancer prognosis and therapy response.
authors.affiliation: Authors' Affiliations: Human Genetics Foundation Torino; Department of Medical Sciences, University of Turin, Turin; Department of Biology, University of Pisa, Pisa; Laboratory of Computational Oncology, Center for Integrated Biology (CIBIO), University of Trento, Trento, Italy; Department of Molecular Biology of Cancer, Institute of Experimental Medicine; Departments of Surgery and Oncology, Thomayer Hospital; Institute of Biology and Department of Medical Genetics; and Department of Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.forename: Fabio
authors.initials: F
authors.lastname: Rosa
authors.forename: Elisa
authors.initials: E
authors.lastname: Barone
authors.forename: Cornelia
authors.initials: C
authors.lastname: Di Gaetano
authors.forename: Jana
authors.initials: J
authors.lastname: Slyskova
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.forename: Miroslav
authors.initials: M
authors.lastname: Levy
authors.forename: Sonia
authors.initials: S
authors.lastname: Garritano
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.forename: Tomas
authors.initials: T
authors.lastname: Buchler
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001665:Binding Sites; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs