title: Inherited variability in a master regulator polymorphism (rs4846126) associates with survival in 5-FU treated colorectal cancer patients.
abstract: BACKGROUND
  Treatment with 5-fluorouracil (5-FU) is known to improve survival in many cancers including colorectal cancer. Response to the treatment, overall survival and recurrence show inter-individual variation.
  
  
  METHODS
  In this study we employed a strategy to search eQTL variants influencing the expression of a large number of genes. We identified four single nucleotide polymorphisms, defined as master regulators of transcription, and genotyped them in a set of 218 colorectal cancer patients undergoing adjuvant 5-FU based therapy.
  
  
  RESULTS
  Our results showed that the minor allele variant of the rs4846126 polymorphism was associated with poor overall and progression-free survival. Patients that were homozygous for the variant allele showed an over two fold increased risk of death (HR 2.20 95%CI 1.05-4.60) and progression (HR 2.88, 95% 1.47-5.63). The integration of external information from publicly available gene expression repositories suggested that the rs4846126 polymorphism deserves further investigation. This variant potentially regulates the gene expression of 273 genes with some of them possibly associated to the patient's response to 5-FU treatment or colorectal cancer.
  
  
  CONCLUSIONS
  Present results show that mining of public data repositories in combination with own data can be a fruitful approach to identify markers that affect therapy outcome. In particular, a genetic screen of master regulators may help in order to search for the polymorphisms involved in treatment response in cancer patients.
authors.affiliation: Human Genetics Foundation, Turin, Italy; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic. Electronic address: barbara.pardini@hugef-torino.org.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.affiliation: Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.affiliation: Human Genetics Foundation, Turin, Italy; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.affiliation: Human Genetics Foundation, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Di Gaetano
authors.affiliation: Human Genetics Foundation, Turin, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rosa
authors.affiliation: Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Carine
authors.initials: C
authors.lastname: Legrand
authors.affiliation: Department of Oncology, General Teaching Hospital, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; First Medical Faculty, Charles University, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000601:surgery; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D002955:Leucovorin; D005472:Fluorouracil
keywords: 5 Fluorouracil (5-FU) chemotherapy; Colorectal cancer; EQTL studies; Genome-wide association studies (GWAS); Master regulators of transcription; Overall survival