title: Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304).
abstract: BACKGROUND
  Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU.
  
  
  METHODS
  The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304).
  
  
  RESULTS
  There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06).
  
  
  CONCLUSIONS
  Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases, Heidelberg, Germany.|German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.affiliation: Southwest Oncology Group Statistical Center, Seattle, WA.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Rankin
authors.affiliation: Department of Surgery, Division of Public Health Sciences and Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Adetunji T
authors.initials: AT
authors.lastname: Toriola
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases, Heidelberg, Germany.|German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Altug-Teber
authors.affiliation: Southwest Oncology Group Statistical Center, Seattle, WA.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Benedetti
authors.affiliation: Oregon Health & Science University, Portland, OR.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Holmes
authors.affiliation: Olathe Regional Oncology Center, Olathe, KS.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Smalley
authors.affiliation: Oregon Health & Science University, Portland, OR.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.affiliation: University of Southern California, Los Angeles, CA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D005492:Folic Acid; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D005472:Fluorouracil
keywords: 5-fluorouracil; MTHFR polymorphism; clinical trial; folate; pharmacogenetics; rectal cancer; survival; toxicity