title: Genetic polymorphisms in 5-Fluorouracil-related enzymes predict pathologic response after neoadjuvant chemoradiation for rectal cancer.
abstract: Many patients with rectal cancer undergo preoperative neoadjuvant chemoradiation, with approximately 70% exhibiting pathologic downstaging in response to treatment. Currently, there is no accurate test to predict patients who are likely to be complete responders to therapy. 5-Fluorouracil is used regularly in the neoadjuvant treatment of rectal cancer. Genetic polymorphisms affect the activity of thymidylate synthase, an enzyme involved in 5-Fluorouracil metabolism, which may account for observed differences in response to neoadjuvant treatment between patients. Detection of genetic polymorphisms might identify patients who are likely to have a complete response to neoadjuvant therapy and perhaps allow them to avoid operation.
  
  
  
  DNA was isolated from whole blood taken from patients with newly diagnosed rectal cancer who received neoadjuvant therapy (n = 50). Response to therapy was calculated with a tumor regression score based on histology from the time of operation. Polymerase chain reaction was performed targeting the promoter region of thymidylate synthase. Polymerase chain reaction products were separated using electrophoresis to determine whether patients were homozygous for a double-tandem repeat (2R), a triple-tandem repeat (3R), or were heterozygous (2R/3R). A single nucleotide polymorphism, 3G or 3C, also may be present in the second repeat unit of the triple-tandem repeat allele. Restriction fragment length polymorphism assays were performed in patients with at least one 3R allele using HaeIII.
  
  
  
  Patients with at least 1 thymidylate synthase 3G allele were more likely to have a complete or partial pathologic response to 5-Fluorouracil neoadjuvant therapy (odds ratio 10.4; 95% confidence interval, 1.3-81.6; P = .01) than those without at least one 3G allele.
  
  
  
  Identification of rectal cancer patients with specific genetic polymorphisms in enzymes involved in 5-Fluorouracil metabolism seems to predict the likelihood of complete or partial pathologic response to preoperative neoadjuvant therapy.
authors.affiliation: Price Institute of Surgical Research, Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, KY; Price Institute of Surgical Research, University of Louisville School of Medicine, University of Louisville, Louisville, KY.
authors.forename: Bailey
authors.initials: B
authors.lastname: Nelson
authors.affiliation: Price Institute of Surgical Research, Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, KY.
authors.forename: Jane V
authors.initials: JV
authors.lastname: Carter
authors.affiliation: Price Institute of Surgical Research, Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, KY.
authors.forename: Maurice R
authors.initials: MR
authors.lastname: Eichenberger
authors.affiliation: Price Institute of Surgical Research, Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, KY.
authors.forename: Uri
authors.initials: U
authors.lastname: Netz
authors.affiliation: Price Institute of Surgical Research, Hiram C. Polk Jr, MD Department of Surgery, University of Louisville, Louisville, KY. Electronic address: s0gala01@louisville.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Galandiuk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059248:Chemoradiotherapy / Q000379:methods; D016208:Databases, Factual; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D000071184:Pharmacogenomic Variants; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012004:Rectal Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D012189:Retrospective Studies; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D005472:Fluorouracil