title: DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity.
abstract: OBJECTIVE
  5-fluorouracil (5-FU) has been widely used since the 1980s, and it remains the backbone of many chemotherapeutic combination regimens. However, its use is often limited by the occurrence of severe toxicity. Although several reports have shown the detrimental effect of some dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) gene polymorphisms in patients undergoing 5-FU-based treatment, they account for only a minority of toxicities.
  
  
  METHODS
  Looking for new candidate genetic variants associated with 5-FU-induced toxicity, we used the innovative genotyping microarray Affymetrix Drug-Metabolizing Enzymes and Transporters (DMET)™ Plus GeneChip that interrogates 1,936 genetic variants distributed in 231 genes involved in drug metabolism, excretion, and transport. To reduce variability, we analyzed samples from colorectal cancer patients who underwent fairly homogenous treatments (i.e., Machover or Folfox) and experienced G3 or G4 toxicity; control patients were matched for therapy and selected from those who did not disclose toxicity (G0-G1).
  
  
  RESULTS
  Pharmacogenetic genotyping showed no significant difference in DPYD and TYMS genetic variants distribution between cases and controls. However, other polymorphisms could account for 5-FU-induced toxicity, with the CHST1 rs9787901 and GSTM3 rs1799735 having the strongest association.
  
  
  CONCLUSIONS
  Although exploratory, this study suggests that genetic polymorphisms not directly related to 5-FU pharmacokinetics and pharmacodynamics are involved in 5-FU-induced toxicity. Our data also indicates DMET™ microarray as a valid approach to discover new genetic determinants influencing chemotherapy-induced toxicity.
authors.affiliation: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Via Gattamelata 64, Padua, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Rumiato
authors.forename: Elisa
authors.initials: E
authors.lastname: Boldrin
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
authors.forename: Daniela
authors.initials: D
authors.lastname: Saggioro
mesh_terms: D020121:5' Untranslated Regions; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D017353:Gene Deletion; D018628:Gene Dosage; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D016254:Mutagenesis, Insertional; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D015238:Sulfotransferases / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D000097811:Carbohydrate Sulfotransferases
chemical_list: D020121:5' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; D005982:Glutathione Transferase; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations; D015238:Sulfotransferases; D013940:Thymidylate Synthase; D000097811:Carbohydrate Sulfotransferases; C483009:GSTM3 protein, human