title: Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.
abstract: BACKGROUND
  Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.
  
  
  METHODS
  Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.
  
  
  RESULTS
  Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻⁶, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively).
  
  
  CONCLUSIONS
  We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.
authors.affiliation: Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Foundation Trust, College House, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Loganayagam
authors.forename: M
authors.initials: M
authors.lastname: Arenas Hernandez
authors.forename: A
authors.initials: A
authors.lastname: Corrigan
authors.forename: L
authors.initials: L
authors.lastname: Fairbanks
authors.forename: C M
authors.initials: CM
authors.lastname: Lewis
authors.forename: P
authors.initials: P
authors.lastname: Harper
authors.forename: N
authors.initials: N
authors.lastname: Maisey
authors.forename: P
authors.initials: P
authors.lastname: Ross
authors.forename: J D
authors.initials: JD
authors.lastname: Sanderson
authors.forename: A M
authors.initials: AM
authors.lastname: Marinaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D003564:Cytidine Deaminase / Q000235:genetics* / Q000502:physiology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D008957:Models, Genetic; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D010597:Pharmacogenetics; D011379:Prognosis; D012307:Risk Factors; D013940:Thymidylate Synthase / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D003564:Cytidine Deaminase; D005472:Fluorouracil