title: Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer.
abstract: BACKGROUND
  There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study.
  
  
  METHODS
  The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed.
  
  
  RESULTS
  MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C-1298C) and diplotypes (CA-TA and TA-TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response.
  
  
  CONCLUSIONS
  MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.
authors: UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA. thomas.fabienne@claudiusregaud.fr
authors: F
authors: F
authors: Thomas
authors: A A
authors: AA
authors: Motsinger-Reif
authors: J M
authors: JM
authors: Hoskins
authors: A
authors: A
authors: Dvorak
authors: S
authors: S
authors: Roy
authors: A
authors: A
authors: Alyasiri
authors: R J
authors: RJ
authors: Myerson
authors: J W
authors: JW
authors: Fleshman
authors: B R
authors: BR
authors: Tan
authors: H L
authors: HL
authors: McLeod
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D011838:Radiation-Sensitizing Agents; D000077146:Irinotecan; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005472:Fluorouracil; D002166:Camptothecin