title: Pharmacogenomics of fluorouracil -based chemotherapy toxicity.
abstract: BACKGROUND
  5- fluorouracil (5-FU), alone or in combination, is the most prevalent and effective chemotherapeutic agent for the treatment of cancers of the head and neck, breast, pancreas and gastrointestinal tract.
  
  
  METHODS
  Three rare DPYD mutations, a splice mutation in intron 14 (c.1905+1G>A) and two nonsynonymous coding variants (c.1679T>G, c.2846A>T), have consistently been associated with severe 5-FU toxicity. A relatively common haplotype, hapB3, containing three intronic polymorphisms (c.483+18G>A; c.680+139G>A; c.959-51T>C) and a synonymous mutation c.1236G>A linked to c.1129-5923C>G, is a major contributor to early onset severe toxicity. TYMS VNTR 2R and TYMS-3'-UTR 6-bp ins-del variants were associated with global toxicity in capecitabine-treated patients. A candidate gene study of capecitabine-related toxicity reported that the s12132152 were strongly associated with hand-foot syndrome (HFS), whereas rs7548189 was associated with diarrhea. The rs2612091 and rs2741171, which are downstream of TYMS and intronic for ENOSF1, were associated with increased global toxicity and HFS.
  
  
  CONCLUSIONS
  Sex-dependent differences, ethnicity, cancer types and 5-FU-based chemotherapy regimens might affect the heterogeneity of genetic variants for predictive 5-FU-related toxicity. Future approaches using genome-wide association analyses may help in identifying additional candidate genes causally involved in the path mechanisms of 5-FU-related toxicity.
authors: University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Division of Medical Oncology , Los Angeles, CA , USA.
authors: Satoshi
authors: S
authors: Matsusaka
authors: Heinz-Josef
authors: HJ
authors: Lenz
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil
keywords: 5-fluorouracil; dihydropyrimidine dehydrogenase; methylene tetrahydrofolate reductase; thymidylate synthase